Patent Application
20250177115
The present technology relates to combinatorial therapies including an implantable damping device and therapeutic agents for treating a condition (e.g., a neurodegenerative condition such as dementia) and associated systems and methods of use. In particular, the present technology is directed to combinatorial therapies including an implantable damping device for positioning at, near, within, around, or in place of at least a portion of an artery and one or more therapeutic agents (e.g., EDG Receptor Family modulators, MMP inhibitors, and senolytic agents) for treating the condition.
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
The heart supplies oxygenated blood to the body through a network of interconnected, branching arteries starting with the largest artery in the body—the aorta. As shown in the schematic view of the heart and selected arteries in
During the systole stage of a heartbeat, contraction of the left ventricle forces blood into the ascending aorta that increases the pressure within the arteries (known as systolic blood pressure). The volume of blood ejected from the left ventricle creates a pressure wave—known as a pulse wave—that propagates through the arteries propelling the blood. The pulse wave causes the arteries to dilate, as shown schematically in
The difference between the systolic blood pressure and the diastolic blood pressure is the “pulse pressure,” which generally is determined by the magnitude of the contraction force generated by the heart, the heart rate, the peripheral vascular resistance, and diastolic “run-off” (e.g., the blood flowing down the pressure gradient from the arteries to the veins), amongst other factors. High flow organs, such as the brain, are particularly sensitive to excessive pressure and flow pulsatility. To ensure a relatively consistent flow rate to such sensitive organs, the walls of the arterial vessels expand and contract in response to the pressure wave to absorb some of the pulse wave energy. As the vasculature ages, however, the arterial walls lose elasticity, which causes an increase in pulse wave speed and wave reflection through the arterial vasculature. Arterial stiffening impairs the ability of the carotid arteries and other large arteries to expand and dampen flow pulsatility, which results in an increase in systolic pressure and pulse pressure. Accordingly, as the arterial walls stiffen over time, the arteries transmit excessive force into the distal branches of the arterial vasculature.
Research suggests that consistently high systolic pressure, pulse pressure, and/or change in pressure over time (dP/dt) increases the risk of dementia, such as vascular dementia (e.g., an impaired supply of blood to the brain or bleeding within the brain). Without being bound by theory, it is believed that high pulse pressure can be the root cause or an exacerbating factor of vascular dementia and age-related dementia (e.g., Alzheimer's disease). As such, the progression of vascular dementia and age-related dementia (e.g., Alzheimer's disease) may also be affected by the loss of elasticity in the arterial walls and the resulting stress on the cerebral vessels. Alzheimer's Disease, for example, is generally associated with the presence of neuritic plaques and tangles in the brain. Recent studies suggest that increased pulse pressure, increased systolic pressure, and/or an increase in the rate of change of pressure (dP/dt) may, over time, cause microbleeds within the brain that may contribute to the neuritic plaques and tangles.
By 2050, it is estimated that at least one in every 85 people will be living with Alzheimer's disease world-wide and more than eight times as many people have shown preclinical symptoms. Additional disease-modifying therapies that will prevent or delay the onset or slow progression of neurological conditions, such as dementia, have been and are being developed. As of March 2020, there are 2,272 clinical trials and/or other related testing ongoing for treatment of Alzheimer's disease, one of several neurological conditions that is becoming increasingly more common as the world's population ages. While the therapeutic agents undergoing testing in these clinical trials may improve memory, behavior, cognition and/or reduce neuropsychiatric symptoms of Alzheimer's disease, additional studies testing the efficacy, safety, and tolerability of these therapeutic agents, and/or use of additional therapeutic agents are needed. Accordingly, there is a need for improved devices, systems, and methods for treating vascular and/or age-related dementia.
According to a first aspect of the invention, there is provided a method for treating and/or preventing one or more effects of a condition in a subject in need thereof, the method comprising:
According to a second aspect of the invention, there is provided a method for treating and/or preventing one or more effects of a condition in a subject in need thereof, the method comprising:
According to a third aspect of the invention, there is provided a method for treating and/or preventing one or more effects of a condition in a subject in need thereof, the method comprising:
According to a fourth aspect of the invention, there is provided a system for treating and/or preventing one or more effects of a condition in a subject in need thereof, the system comprising:
According to a fifth aspect of the invention, there is provided a system for treating and/or preventing one or more effects of a condition in a subject in need thereof, the system comprising:
According to a sixth aspect of the invention, there is provided a method for treating a patient having a condition comprising:
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.
Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed on illustrating clearly the principles of the present disclosure.
The present technology is directed to combinatorial therapies including an implantable damping device and a therapeutic agent (e.g., a EDG Receptor Family modulators, MMP inhibitors, and senolytic agents) for treating and/or preventing the progression of a condition, including neurological conditions such as dementia (e.g., vascular dementia and age-related dementia), and associated systems and methods of use. Some embodiments of the present technology, for example, are directed to combinatorial device and therapies including damping devices having an anchoring member and a flexible, compliant damping member having an outer surface and an inner surface defining a lumen configured to direct blood flow. The inner surface is configured such that a cross-sectional dimension of the lumen varies. For example, the outer surface and the inner surface can be separated from each other by a distance that varies along the length of the damping member. The damping member can further include a first end portion, a second end portion opposite the first end portion, and a damping region between the first and second end portions. The distance between the outer surface and the inner surface of the damping member can be greater at the damping region than at either of the first or second end portions. When blood flows through the damping member during systole, the damping member absorbs a portion of the pulsatile energy of the blood to reduce the magnitude of the pulse pressure transmitted to a portion of the blood vessel distal to the damping device. Additional embodiments of the present technology, for example, are directed to combinatorial device and therapies including therapeutic agents (e.g., EDG Receptor Family modulators, MMP inhibitors, and senolytic agents) that have been developed or are currently being developed to treat or otherwise slow the effects of neurological conditions. These therapeutic agents, and other therapeutic agents derived from and/or otherwise based upon these therapeutic agents, are included in embodiments of the present technology. Specific details of several embodiments of the technology are described below with reference to
With regard to the terms “distal” and “proximal” within this description, unless otherwise specified, the terms can reference a relative position of the portions of a damping device and/or an associated delivery device with reference to an operator, direction of blood flow through a vessel, and/or a location in the vasculature. For example, in referring to a delivery catheter suitable to deliver and position various damping devices described herein, “proximal” refers to a position closer to the operator of the device or an incision into the vasculature, and “distal” refers to a position that is more distant from the operator of the device or further from the incision along the vasculature (e.g., the end of the catheter).
As used herein, “artery” and “arteries that supply blood to the brain,” include any arterial blood vessel (or portion thereof) that provides oxygenated blood to the brain. For example, “arteries” or “arteries that supply blood to the brain” can include the ascending aorta, the aortic arch, the brachiocephalic trunk, the right common carotid artery, the left common carotid artery, the left and right internal carotid arteries, the left and right external carotid arteries, and/or any branch and/or extension of any of the arterial vessels described above.
As used herein, the terms “therapeutic agent”, “agent”, “therapy”, and “therapies” are used interchangeably within this description to refer to drugs and/or therapies described herein, including EDG Receptor Family Modulators, an MMP inhibitors, and/or a senolytic agents. Agents and therapies may be composed of a wide variety of substances including, but not limited to, sugars (or other small molecules), synthetic chemicals, proteins or peptides, nucleic acids, complex combinations of those substances, or may be living entities such as cells or tissues. Agents and therapies include a wide variety of products and treatments that may be isolated from or otherwise derived from natural sources (e.g., human, animal, plant, microorganism) using recombinant, synthetic, or other biotechnology methods and technologies. For example, a peptide or other natural molecule that is synthetically produced may be considered an agent in accordance with this disclosure.
The terms “recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, etc. Preferably, the mammal is human.
With regard to the term “neurological condition” within this description, unless otherwise specified, the term refers to a condition, a disorder, and/or a disease of the brain, spine, and nerves connecting the brain and the spine. Neurological conditions include, but are not limited to dementia (e.g., vascular, frontotemporal, Lewy body), Alzheimer's disease, Huntington's disease, cognitive impairment, Parkinson's disease, neuralgia, tumor, cancer, stroke, aneurysm, epilepsy, headache, and/or migraine.
A “subject in need thereof” as used herein refers to a mammalian subject, preferably a human, who has been diagnosed with a neurologic condition, is suspected of having a neurologic condition, and/or exhibits one or more symptoms or risk factors associated with a neurologic condition.
The terms “treating” and “treatment” in relation to a given condition, disease, or disorder are used interchangeably and include, but are not limited to, inhibiting the disease or disorder, for example, arresting the development or rate of development of the condition, disease, or disorder; relieving the condition, disease, or disorder, for example, causing regression of the condition, disease, or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, arresting, relieving, preventing, or causing regression of at least one of the symptoms of the disease or disorder.
The terms “preventing” and “prevention” in relation to a given condition, disease, or disorder are used interchangeably and include, but are not limited to, preventing or delaying the onset of its development if none had occurred; preventing or delaying the condition, disease, or disorder from occurring in a subject that may be predisposed to the condition, disease, or disorder but has not yet been diagnosed as having the condition, disease; or disorder, and/or preventing or delaying further development of the condition, disease, or disorder if already present.
As used herein, “route” in relation to administration of one or more therapies, such as a therapeutic agent (e.g., drug), refers to a path by which the therapeutic agent is delivered to a subject, for example, a subject's body. A route of therapeutic administration include enteral and parenteral routes of administration. Enteral administration includes oral, rectal, intestinal, and/or enema. Parenteral includes topical, transdermal, epidural, intracerebral, intracerebroventricular, epicutaneous, sublingual, sublabial, buccal, inhalational (e.g., nasal), intravenous, intraarticular, intracardiac, intradermal, intramuscular, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intravitreal, subcutaneous, perivascular, implantation, vaginal, otic, and/or transmucosal.
In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein is to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term “about” means ±20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms “a” and “an” as used herein refer to “one or more” of the enumerated regions. Words using the singular or plural number also include the plural or singular number, respectively. Use of the word “or” in reference to a list of two or more items covers all of the following interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list. Furthermore, the phrase “at least one of A, B, and C, etc.” is intended in the sense that one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include, but not be limited to, systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general, such a construction is intended in the sense that one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include, but not be limited to, systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). As used herein, the terms “include,” “have,” and “comprise” are used synonymously, which terms and variants thereof are intended to be construed as non-limiting. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.
The present invention has been described in terms of particular embodiments found or proposed by the present inventor to comprise preferred modes for the practice of the invention. It will be appreciated by those of skill in the art that, in light of the present disclosure, numerous modifications and changes can be made in the particular embodiments exemplified without departing from the intended scope of the invention. For example, due to codon redundancy, changes can be made in the underlying DNA sequence without affecting the protein sequence. Moreover, due to biological functional equivalency considerations, changes can be made in protein structure without affecting the biological action in kind or amount. All such modifications are intended to be included within the scope of the appended claims.
While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
The damping member 102 shown in
In the embodiment shown in
In the embodiment shown in
In some embodiments, a biocompatible gel or liquid may be located between the wall of the artery A and the outer surface 115 of the damping member 102 to prevent the ingression of blood into the void defined between the first anchoring member 104a, the second anchoring member 104b, the damping member 102, and the inner wall of the artery CA. Alternatively, air or another gas may be located between the internal wall of the carotid artery CA and the damping member 102 to prevent the ingression of blood into the void.
In some embodiments, instead of the damping device 100′ having a separate outer layer 130, the damping member 102 can be molded, formed, or otherwise extruded to enclose a cavity. For example, as shown in
The damping member 202 shown in
In the embodiment shown in
In the embodiment shown in
In some embodiments, one or both of the anchoring members 204a-204b can optionally include one or more fixation elements 205 (
As shown in
Image guidance, e.g., computed tomography (CT), fluoroscopy, angiography, intravascular ultrasound (IVUS), optical coherence tomography (OCT), or another suitable guidance modality, or combinations thereof, may be used to aid the clinician's positioning and manipulation of the damping device 200. For example, a fluoroscopy system (e.g., including a flat-panel detector, x-ray, or c-arm) can be rotated to accurately visualize and identify the target treatment site. In other embodiments, the treatment site can be determined using IVUS, OCT, and/or other suitable image mapping modalities that can correlate the target treatment site with an identifiable anatomical structure (e.g., a spinal feature) and/or a radiopaque ruler (e.g., positioned under or on the patient) before delivering the damping device 200. Further, in some embodiments, image guidance components (e.g., IVUS, OCT) may be integrated with the delivery catheter and/or run in parallel with the delivery catheter to provide image guidance during positioning of the damping device 200.
Once the guide catheter 604 is positioned at the treatment site, the guidewire 602 may be withdrawn. As shown in
In some procedures the clinician may want to stretch or elongate the damping device 200 before deploying the proximal second anchoring member 204b against the arterial wall. To address this need, the delivery assembly 610 and/or damping device 200 can optionally include a tensioning mechanism for pulling or providing a tensile stress on the second anchoring member 204b, thereby increasing the length of the damping member 202 and/or a distance between the first and second anchoring members 204a, 204b. For example, as shown in
In other embodiments, other tensioning mechanisms may be utilized. For example, in some embodiments, the damping device 200 includes a releasable clasp, ring, or hook which is selectively releasable by the operator. The clasp, ring or hook may be any type that permits securement of the thread to the second anchoring member 204b, and which can be selectively opened or released to disengage the thread from the second anchoring member 204b. The releasing can be controlled by the clinician from an extracorporeal location. Although the tensioning mechanism is described herein with respect to the second anchoring member 204b, it will be appreciated that other portions of the damping device 200 and/or the delivery assembly 610 (such as the first anchoring member 204a) can be coupled to a tensioning mechanism.
In certain embodiments, the damping member 202 and/or individual anchoring members 204a, 204b may be self-expanding. For example, the delivery assembly 610 can include a delivery sheath (not shown) that surrounds and radially constrains the damping device 200 during delivery to the treatment site. Upon reaching the treatment site, the delivery sheath may be at least partially withdrawn or retracted to allow the damping member 202 and/or the individual anchoring members 204a, 204b to expand. In some embodiments, expansion of the anchoring members 204 may drive expansion of the damping member 202. For example, the anchoring members 204 may be fixedly attached to the damping member 202, and expansion of one or both anchoring 204 pulls or pushes (depending on the relative positioning of the damping member 202 and anchoring members 204) the damping member 202 radially outwardly.
As best shown in
In some procedures, it may be beneficial to deliver multiple damping devices 200 to multiple arterial locations. For example, after deploying a first damping device 200 at a first arterial location (e.g., the left or right common carotid artery, an internal or external carotid artery, the ascending aorta, etc.), the clinician may then position and deploy a second damping device 200 at a second arterial location different than the first arterial location (e.g., the left or right common carotid artery, an internal or external carotid artery, the ascending aorta etc.). In a particular application, a first damping device is deployed in the left common carotid artery and the second damping device is deployed in the right common carotid artery. In other embodiments, two or more damping devices 200 may be delivered simultaneously.
In some embodiments, an additional stent of larger diameter may be placed within the vessel prior to deployment of the damping device 200 to expand the diameter of the vessel in preparation for the device. Subsequently, the damping device 200 can be deployed within the larger stent. This may assist to reduce impact on the residual diameter of the vessel, and thereby reduce impact on blood flow rate.
The anchoring members 1204a and 1204b can be generally similar to the anchoring members 104a and 104b described with respect to
In the deployed state, the damping member 1202 is configured to be wrapped along the circumference of an artery that supplies blood to the brain. For example, in the embodiment shown in
In some embodiments (not shown), the damping device can be a biocompatible gel which is injected around a portion of the left or right carotid artery or the brachiocephalic trunk. The gel increases the external pressure acting on the artery and thus reduces the external diameter of the artery. As blood pressure increases within the artery, the gel elastically deforms, such that the artery radially expands during the systole stage and radially contracts during the diastole stage.
The structural member 1604 can be a generally cylindrical structure configured to expand from a low-profile state to a deployed state. The structural member 1604 is configured to provide structural support to secure the damping device 1600 to a selected region of the artery. In some embodiments, the structural member 1604 can be a stent formed from a laser cut metal, such as a superelastic and/or shape memory material (e.g., Nitinol) or stainless steel. All or a portion of the structural member 1604 can include a radiopaque coating to improve visualization of the device 1600 during delivery, and/or the structural member 1604 may include one or more radiopaque markers. In other embodiments, the structural member 1604 may comprise a mesh or woven (e.g., a braid) construction in addition to or in place of a laser cut stent. For example, the structural member 1604 can include a tube or braided mesh formed from a plurality of flexible wires or filaments arranged in a diamond pattern or other configuration. In some embodiments, all or a portion of the structural member 1604 can be covered by a graft material (such as Dacron) to promote sealing with the vessel wall. Additionally, all or a portion of the structural member 1604 can include one or more biomaterials.
In the embodiment shown in
In the embodiment shown in
In the embodiment shown in
Referring to
When the damping member 1602 deforms in response to the pulse wave, the shape of the structural member 1604 may remain generally unchanged, thereby providing the support to facilitate redistribution of the fluid particles within and along the damping member 1602. In other embodiments, the structural member 1604 may also deform in response to the local fluid stress.
As best shown in
The damping device 1800 may be configured to wrap around the circumference of the artery A so that the inner surface 1812 (
In addition to providing the implantable damping device, the present technology includes providing therapeutic agents for treating neurological disorders. One of ordinary skill in the art will understand that the therapeutic agents discussed herein are illustrative of the type of therapeutic agents in the present technology, and that the present technology is not limited to the therapeutic agents explicitly discussed herein. For example, therapeutic agents not explicitly described herein but that are within the classes of therapeutic agents provided herein and/or treat the neurological conditions discussed herein are included in the present technology.
Therapeutic agents for treating neurological conditions, such as neurocognitive and/or neurodegenerative disorders, include therapeutic agents approved for use in human subjects by the Food and Drug Administration of the United States of America (“FDA”), therapeutic agents currently in clinical trials to investigate their use in human subjects such as clinical trials governed by the FDA or other similar organizations in other countries, pre-clinical therapeutic agents, and any other therapeutic agent for treating a neurological condition, or intended to treat a neurological condition such as investigative therapeutic agents, therapeutic agents that are undergoing development or otherwise being considered for development, and therapeutic agents that have been identified as potentially useful for treating or intending to treat the neurological condition. Examples of neurological conditions, such neurocognitive, neurodegenerative, or other neurological disorders include, but are not limited to, Alzheimer's disease, mild Alzheimer's disease, prodromal Alzheimer's disease, mild cognitive impairment, cerebral amyloid angiopathy, frontotemporal dementia, vascular dementia, age-related dementia, amyloidosis, Lewy body disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich's ataxia, and traumatic brain injury. In some embodiments, these therapeutic agents represent more than one class of therapeutic agents, more than one mechanism of action, more than one therapeutic target, and more than one therapeutic purposes.
The therapeutic agents discussed herein have different therapeutic purposes, such as disease modifying therapeutic agents, symptomatic cognitive enhancers, and/or symptomatic agents addressing neuropsychiatric and behavioral changes. Disease modifying therapeutic agents, for example, alter the pathophysiology of the neurological condition. Symptomatic therapeutic agents, for example, mitigate and/or alleviate symptoms associated with the neurological condition. In some embodiments, a therapeutic agent is a disease modifying therapy and a symptomatic therapy. In some embodiments, a therapeutic agent may include more than one therapeutic agent.
In some embodiments, therapeutic agents of the present technology are members of general classes of therapeutic agents which include, but are not limited to, EDG Receptor Family modulators, MMP inhibitors, and senolytic agents.
In some embodiments, therapeutic agents of the present technology have different mechanisms of action. In some embodiments, a therapeutic agent is selected for administration to a subject in need thereof based on its mechanism of action. For example, some therapeutic agents for treating neurological conditions such as Alzheimer's disease prevent abnormal cleavage of amyloid precursor protein in a subject's brain. In some embodiments, therapeutic agents prevent expression and/or accumulation of β-amyloid protein (Aβ) in the subject's brain. For example, some therapeutic agents for treating neurological conditions such as Alzheimer's disease reduce systemic inflammation, blood brain barrier inflammation, systemic inflammation, blood brain barrier inflammation, or neuroinflammation in the subject. In some embodiments, therapeutic agents for treating neurological conditions such as Alzheimer's disease have an endothelial protective effect. In some embodiments, therapeutic agents treat, prevent, or delay Alzheimer's disease, other neurological conditions, or cognitive decline by decreasing inflammation (e.g., blood brain barrier inflammation, neuroinflammation, systemic inflammation), decreasing reactive oxygen species (e.g., oxidative stress), decreasing ischemia, and/or decreasing amyloid beta. For example, inflammation can be decreased by directly or indirectly reducing a level of one or more cytokines, chemokines, and/or inflammatory markers in the subject (e.g., circulating or in the subject's cerebral spinal fluid (CSF)), including VCAM-1, ICAM-1, TNFα, TGF-β, IL-6, IL-8, IL-1β, IL-12, and NF-κB, and/or administering a peptide-based therapeutic to the subject, such as an IL-1Rα derivative (e.g., Anakinra®). Reactive oxygen species can be increased in the subject relative to before the subject has the condition or compared to a subject who does not have the condition. In other embodiments, therapeutic agents treat, prevent, or delay Alzheimer's disease, other neurological conditions, or cognitive decline by inhibiting MMPs, eliminating senescent cells, improving tight junctions, or inducing transcriptional activation of TIMP.
Any of the therapeutic agents described herein, as well as other therapeutic agents which are members of the general classes of therapeutic agents described herein, are administered to the subject in need thereof at a therapeutically effective dose before, during, or after positioning the implantable damping device within a subject, such as but not limited to a subject having elevated forward compression wave intensity (FCWI) or elevated pulse pressure. Non-limiting elevated pulse pressure values include top-quartile carotid FCWI (mmHg m/s3) of at least about 10,000, a systolic blood pressure (mmHg) of at least about 125 mmHg, a pulse pressure of at least about 50 mmHg, a diastolic blood pressure of at most about 70 mmHg, and/or a mean arterial pressure of at least about 88 mmHg. In some embodiments, a carotid FCWI range (mmHg m/s3) of at least about 10,000, a systolic blood pressure (mmHg) of at least about 135 mmHg, a pulse pressure of at least about 55 mmHg, a diastolic blood pressure of at most about 75 mmHg, and/or a mean arterial pressure of at least about 95 mmHg. Without intending to be bound by any particular dose or administration regimen, a therapeutically effective dose is an amount of the therapeutic agent that, when administered to the subject in need thereof, treats or at least partially treats, reduces the effects of, or at least partially reduces the effects of, the subject's condition (e.g., neurodegenerative condition, cognitive decline). The therapeutically effective dose for each therapeutic agent is selected based upon a variety of factors, including but not limited to, one or more characteristics of the therapeutic agent (e.g., bioactivity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (e.g., age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), and the route of administration.
Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lysophospholipids (LPLs) that can have similar effects on cellular response by acting on a common family of receptors. The Endothelial Cell Differentiation Gene (EDG) Receptors are a family of G-Protein Coupled Receptor (GPCR) that function as receptors for both S1P and LPA. EDG receptors, identified in Table 1 below, are classed into two sub-families and named in accordance with the ligand to which they bind (S1P or LPA).
Activation of the EDG receptors by S1P or LPA has multiple effects on cells, including proliferation, cell survival, migration, differentiation and cytoskeletal organization, and cytokine secretion. In addition to these effects, these S1P and LPA have been implicated in many pathophysiological processes, including inflammatory vascular disease, autoimmune disease, fibrotic disease, cancer, inflammation, and bone disease. Thus, EDG receptor family modulators (e.g., S1P receptor agonists, LPA receptor agonists) may be used in accordance with the embodiments described herein.
S1P has been shown to enhance endothelial barrier function, stimulate endothelial NO release through Akt-mediated phosphorylation of eNOS, and reconstitute high density lipoproteins. S1P also has anti-inflammatory properties and exerts protective effect against endotoxin-induced lung injury. Moreover, S1P exhibits a potent effect on the differentiation of adipose-derived stem cells into endothelial-like cells and upregulation of eNOS in these cells. These properties of S1P may contribute to its endothelial protective effect. Thus, in some embodiments, the EDG receptor family modulator is an S1P receptor agonist.
In some embodiments, the S1P receptor agonist is fingolimod (also known as FTY720, or Gilenya®), siponimod (Mayzent®), ozanimod, or ponesimod. These S1P receptor agonists may be beneficial to blood brain barrier integrity through activation of S1P1 and/or S1P5. In certain embodiments, the S1P receptor agonist is fingolimod (also known as FTY720, or Gilenya®). FTY720, after phosphorylation to FTY720-P, is an orally active S1P mimetic. Fingolimod was developed for therapy in the field of autoimmune diseases and organ transplantation, and is a clinically approved immunomodulating therapy for multiple sclerosis. Fingolimod shows potent anti-inflammatory effects and S1P receptor activation may lead to inhibition of the progression of inflammatory vascular diseases like atherosclerotic lesions. Fingolimod has also been shown to promote angiogenesis, attenuate ischemic brain damage, repair brain injuries, and may have the ability to reverse blood-brain-barrier damage (or to preserve BBB integrity). Fingolimod has also been shown to attenuate infection-induced enhancement of Aβ Accumulation. In other embodiments, the S1P receptor agonist is siponimod. Similar to fingolimod, siponimod has been indicated to strengthen BBB properties by modulating S1P1 and S1P5.
EDG receptor family modulators can be administered at any therapeutically effective dose that is effective to treat the subject in need thereof. In certain embodiments, the effective dose corresponds to an FDA-approved dose or any off-label use within the standard of care known to those skilled in the art. For example, in certain embodiments where fingolimod and/or siponimod is used, the fingolimod and/or siponimod may be administered as recommended at a dose of 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg, or 2 mg. In other embodiments where ponesimod is used, the ponesimod may be administered as recommended at a dose of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, or 20 mg. In other embodiments where ozanimod is used, the ozanimod may be administered as recommended at a dose of 0.23 mg, 0.46 mg, or 0.92 mg.
In other embodiments, the effective dose corresponds to a dose that is lower or higher than the FDA-approved dose. For example, in some embodiments, a dose of an EDG receptor family modulator ranges from about 1 to about 500 μg/kg of body weight. For example, dosages are between about 1 μg/kg and about 10 μg/kg, between about 0.1 μg/kg and about 50 μg/kg, between about 1 μg/kg and about 100 μg/kg, between about 1 μg/kg and about 150 μg/kg, or between about 1 μg/kg and about 200 mg/kg, about 1 μg/kg and about 250 μg/kg, about 1 μg/kg and about 300 μg/kg, about 1 μg/kg and about 350 μg/kg, about 1 μg/kg and about 400 μg/kg, about 1 μg/kg and about 450 μg/kg, about 1 μg/kg and about 500 μg/kg, about 1 μg/kg and about 750 μg/kg, or about 1 μg/kg and about 1 mg/kg, or about 1 μg/kg and about 2 mg/kg. For example, dosages also include one or more doses of about 1 μg/kg, about 2.5 μg/kg, about 5 μg/kg, about 10 μg/kg, about 20 μg/kg, about 30 μg/kg, about 40 μg/kg, about 50 μg/kg, about 100 μg/kg, about 150 μg/kg, about 200 μg/kg, about 250 μg/kg, about 300 μg/kg, about 350 μg/kg, about 400 μg/kg, about 450 μg/kg, about 500 μg/kg, about 750 μg/kg, about 1 mg/kg, or about 2 mg/kg. (or any combination thereof). In some embodiments, the EDG receptor family modulators are administered at a flat dose of less than about 0.001 mg, about 0.001 mg, about 0.01 mg, about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, or higher than about 20 mg.
In some embodiments, the EDG receptor family modulator is administered once daily, twice daily, or more than twice daily. In other embodiments, the EDG receptor family modulator is administered less often, e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week. In certain embodiments, the EDG receptor family modulator may be titrated, wherein the EDG receptor family modulator is administered starting at a low dose, and is then raised incrementally until the desired effective dose is reached. In some embodiments, the EDG receptor family modulator is administered chronically. In some embodiments, dosages of EDG receptor family modulators are administered in one or more separate administrations or by continuous infusion.
Matrix metalloproteinases (MMPs) encompass 23 secreted or cell surface proteases that act together and with other protease classes to turn over the extracellular matrix, cleave cell surface proteins and alter the function of many secreted bioactive molecules. In the vasculature, MMPs influence the migration proliferation and apoptosis of vascular smooth muscle, endothelial cells and inflammatory cells, thereby affecting intima formation, atherosclerosis and aneurysms. MMP inhibitors have thus been investigated for use in treating vascular diseases. For example, naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracyclines, chemically-synthesized small molecular weight MMP inhibitors (MMPs) and inhibitory antibodies have all been shown to have effects in animal models of vascular disease. MMP inhibitors may therefore be used in accordance with the embodiments described herein. In some embodiments, the MMP inhibitor is ilomastat, marimastat, prinomastat, batimastat, cipemastat, andecaliximab, or doxycycline. In certain embodiments, the MMP inhibitor is doxycycline.
In addition to such agents that directly inhibit MMPs, other agents may act to indirectly inhibit MMP-mediated processes. For example, glucocorticoids have been investigated as a therapeutic intervention for protecting tight junctions and avoiding BBB disruption in a number of cells and animal models. Glucocorticoids, such as dexamethasone, hydrocortisone, and corticosterone, induce improved tight junctions through an increased level of tight junction proteins in vascular endothelial cells. This improvement in the tight junctions by glucocorticoids is also associated with a rearrangement of the cytoskeleton. Moreover, dexamethasone in particular has been shown to inhibit the cytokine-induced upregulation of MMP-9. Dexamethasone also induces transcriptional activation of TIMP-1 (tissue inhibitor of metalloproteinase-1) and TIMP-3, which may block MMP-9-mediated degradation of tight junction proteins. Additionally, dexamethasone suppresses JMJD3 gene activation via a putative negative glucocorticoid response element and maintains integrity of tight junctions in brain microvascular endothelial cells. Further, dexamethasone administration following BBB disruption has been found to expedite the restoration of BBB integrity and to prevent a subsequent elevation in the production of inflammatory markers. Thus, glucocorticoids like dexamethasone may be used in accordance with the embodiments described herein to serve as both an anti-inflammatory agent as well as an indirect MMP inhibitor.
MMP inhibitors, whether direct or indirect can be administered at any therapeutically effective dose that is effective to treat the subject in need thereof. In certain embodiments, the effective dose corresponds to an FDA-approved dose or any off-label use within the standard of care known to those skilled in the art. For example, in some embodiments, where doxycycline is used, the doxycycline may be administered as recommended at a dose of 20 mg, 25 mg, 40 mg, 50 mg, 60 mg, 75 mg. 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 240 mg, or 300 mg; a daily dosage of 100 mg/day, 100-200 mg/day, or 200 mg/day. In other embodiments where dexamethasone is used, the dexamethasone may be administered as recommended at a dose of 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 7 mg, 8 mg, 10 mg, 20 mg; a dose within a range of 4-8 mg, 8-12 mg, 4-24 mg, 10-100 mg; a daily dosage of 0.2-6 mg/day, 0.75-9 mg/day, 3 mg/day, 30 mg/day; or a dose by weight of 1-6 mg/kg or 3 mg/kg.
In other embodiments, the effective dose corresponds to a dose that is lower or higher than the FDA-approved dose. For example, in some embodiments, a dose of an MMP inhibitor ranges from about 0.1 to about 10 mg/kg of body weight. For example, dosages are between about 0.1 mg/kg and about 1 mg/kg, between about 0.1 mg/kg and about 2 mg/kg, between about 0.1 mg/kg and about 3 mg/kg, between about 0.1 mg/kg and about 4 mg/kg, between about 0.1 mg/kg and about 5 mg/kg, between about 0.1 mg/kg and about 6 mg/kg, between about 0.1 mg/kg and about 7 mg/kg, between about 0.1 mg/kg and about 8 mg/kg, between about 0.1 mg/kg and about 9 mg/kg, or between about 0.1 mg/kg and about 10 mg/kg. For example, dosages also include one or more doses of about 0.1 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg, about 10 mg/kg or more than about 10 mg/kg (or any combination thereof). In some embodiments, the MMP inhibitor is administered at a flat dose of about 0.1 mg, about 1.5 mg, about 0.2 mg, about 2.5 mg, about 0.3 mg, about 3.5 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 400 mg, about 500 mg, about 1000 mg, or higher.
In some embodiments, the MMP inhibitor is administered once daily, twice daily, or more than twice daily. In other embodiments, the EDG receptor family modulator is administered less often, e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week. In certain embodiments, the EDG receptor family modulator may be titrated, wherein the EDG receptor family modulator is administered starting at a low dose, and is then raised incrementally until the desired effective dose is reached. In some embodiments, the MMP inhibitor is administered chronically. In some embodiments, dosages of the MMP inhibitor are administered in one or more separate administrations or by continuous infusion.
Senolytic agents are molecules that selectively eliminate senescent cells and have typically been investigated as candidates for treating age-related diseases. Non-limiting examples of senolytic agents that can be used in accordance with the embodiments described herein include, but are not limited to, FOXO4-related peptides, bcl-2 inhibitors, Src tyrosine kinase inhibitors, USP7 (Ubiquitin-specific processing protease 7) inhibitors, dasatinib, quercetin, Fisetin, Navitoclax, Piperlongumine, Azithromycin, Roxithromycin, SSK1 (senescence-specific killing compound 1), Crispr/Cas9 used to knockout BIRC5 or other gene sequences (e.g., cancer or damage marker gene sequences), and kidney-type glutaminase 1 (GLS1) inhibitors.
In some embodiments, a combination of senolytic agents can be used in accordance with the methods and treatments discussed herein. In some embodiments, the combination of senolytic agents is a combination of dasatinib and quercetin (D+Q). D+Q has been found to alleviate age-related brain inflammation, Aβ-associated oligodendrocyte progenitor cell senescence, and cognitive deficits in an Alzheimer's disease model.
Senolytic agents (alone or in combination) can be administered at any therapeutically effective dose that is effective to treat the subject in need thereof. In certain embodiments, the effective dose corresponds to an FDA-approved dose or any off-label use within the standard of care known to those skilled in the art. For example, in some embodiments, where dasatinib is used, the dasatinib may be administered as recommended at a dose of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg, 180 mg. In other embodiments, where quercetin is used, the quercetin may be administered as recommended at a dose of 400 mg, 500 mg, 1000 mg, or between 400-1400 mg. In certain embodiments where a combination D+Q is used, the D+Q may be administered at a dose of 100 mg dasatinib in combination with 1000 mg of quercetin, or any combination of recommended doses discussed above.
In other embodiments, doses of a senolytic agent (alone or in combination) ranges from about 0.0001 to about 500 mg/kg of body weight. For example, dosages are between about 0.1 mg/kg and about 500 mg/kg, between about 0.1 mg/kg and about 250 mg/kg, between about 0.1 mg/kg and about 100 mg/kg, between about 0.1 mg/kg and about 50 mg/kg, or between about 0.1 mg/kg and about 25 mg/kg. For example, dosages also include one or more doses of about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90/mg/kg, about 100 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, or about 500 mg/kg (or any combination thereof). In some embodiments, a senolytic agent (alone or in combination) is administered at a flat dose of about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 500 mg, about 1000 mg, or higher. For example, the senolytic agent (alone or in combination) is administered in one to fifty doses (e.g., the therapy may be delivered in a single dose, in two doses, in three doses, in four doses, in five doses, etc.). In some embodiments, the total dose administered is in the range of about 25 mg to about 5000 mg or higher, of about 50 mg to about 2500 mg, of about 50 mg to about 2000 mg, about 50 mg to about 1500 mg, about 50 mg to about 1000 mg, about 50 mg to about 500 mg, about 50 mg to about 100 mg, or any other range having a therapeutic effect on the subject's condition. For example, the total dose administered can be about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 5000 mg, or higher. In some embodiments, the senolytic agent (alone or in combination) is administered chronically. In some embodiments, dosages of senolytic agent (alone or in combination) are administered in one or more separate administrations or by continuous infusion.
One skilled in the art will understand that the foregoing therapies and accompanying description is for illustrative purposes and does not limit the therapies that may be provided in certain embodiments of the present technology. Accordingly, any therapy useful in or designed to treat a neurological condition, such as a neurodegenerative condition, may be present in certain embodiments of the present technology.
Reducing a subject's pulse pressure with the implantable damping devices has subsequent downstream impacts on other factors that contribute to onset, duration, and/or progression of the subject's condition (e.g., neurological condition). Combining use of devices of the present disclosure to reduce the subject's pulse pressure with therapeutic agents that, when administered to the subject, enhance an effect of reduced pulse pressure on certain outcomes results in a greater reduction and prevention of onset, duration, and/or progression of the subject's neurological condition. Reducing these outcomes results in reduced inflammation (e.g., neuroinflammation, systemic inflammation, blood brain barrier inflammation), decreasing reactive oxygen species (e.g., oxidative stress), reduced ischemia, restoring blood brain barrier integrity, and other benefits. This occurs in subjects suffering from conditions such as progressive cognitive dysfunction and dementia. Without intending to be limiting, subjects having a FCWI value in the top quartile are thought to benefit from a reduction in the FCWI, systolic acceleration time, systolic pressure, and/or pulse pressure value achieved with the implantable damping devices of the present disclosure.
Several biological pathways, for example such as those described herein, may contribute to a neurological condition (e.g., dementia). Without intending to be bound by any particular theory, it is thought that interfering (e.g., altering, effecting, impairing, inhibiting, reducing, or otherwise changing the function of) two or more biological pathways is more effective for treating, preventing, or otherwise reducing the subject's neurological condition, and/or symptoms thereof, rather than interfering with a single biological pathway. In this way, the effects of combining the implantable damping device and at least one therapeutic agent of the present technology may be complementary, additive or even synergistic when compared to an effect of the implantable damping device and the therapeutic agent alone. Accordingly, combining the implantable damping devices with one or more therapeutic agents that affect these other factors further treats and/or slows one or more effects of the condition.
As described above, combinatorial therapies of the present technology include an implantable damping device and a therapeutic agent for treating and/or preventing the progression of the condition. Some embodiments of the present technology, for example, are directed to combinatorial therapies including the implantable damping devices described above under Headings I-III and one or more therapeutic agents that target these factors. Some of these therapeutic agents are described above under Heading IV and include, but are not limited to, EDG Receptor Family Modulators, MMP inhibitors, and senolytic agents. When combined, the implantable damping devices and therapeutic agents of the present technology have a greater effect on treating and/or preventing one or more aspects of the condition upon a subject when compared either to the effects of the implantable damping device or therapeutic agent alone. For example, providing an implantable damping device that reduces the subject's pulse pressure and a therapeutic agent that reduces systemic inflammation and promotes BBB integrity, thereby treating and/or preventing progressive cognitive dysfunction and dementia. Subjects who have elevated pulse pressure or subjects that would otherwise benefit from having reduced pulse pressure may also have a blood brain barrier with increased permeability, one or more microbleeds, increased inflammation, increased oxidative stress, or other vascular dysfunction. The implantable damping device can be provided to these subjects having elevated pulse pressure or subjects that would otherwise benefit from having reduced pulse pressure before, after, or concurrently with a therapeutic agent, such as an EDG Receptor Family Modulator, MMP inhibitor, and senolytic agent.
Methods of the present disclosure include methods for treating a patient having a condition including the steps of, (a) determining or having determined whether the patient has an elevated pulse pressure or elevated pulse wave intensity/FCWI and a history of blood brain barrier dysregulation or permeability, decreasing reactive oxygen species (e.g., oxidative stress), decreasing microbleeds, decreasing inflammation (e.g., systemic inflammation, blood brain barrier inflammation, neuroinflammation), decreasing the level of at least one circulating or cerebral spinal fluid (CSF) cytokine, or a combination thereof by, (i) obtaining or having obtained information which indicates that the patient has the elevated pulse pressure or elevated pulse wave intensity/FCWI and has previously had symptoms of blood brain barrier dysregulation or permeability, oxidative stress, microbleeds, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof and/or was previously diagnosed with a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof; and/or (ii) monitoring or having monitored the subject for the elevated pulse pressure or elevated pulse wave intensity/FCWI and symptoms of blood brain barrier dysregulation or permeability, oxidative stress, a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof. In some embodiments, the methods also include, (b) if the patient has previously had symptoms of blood brain barrier dysregulation or permeability, oxidative stress, a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof, was previously diagnosed with a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof, and/or symptoms of blood brain barrier dysregulation or permeability, oxidative stress, a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof were monitored, then (i) providing an EDG Receptor Family Modulator, an MMP inhibitor, or a senolytic agent to the patient, and (ii) providing a device for treating and/or preventing one or more effects of the condition. In some embodiments, the methods further include, (c) if the patient has not had symptoms of blood brain barrier dysregulation or permeability, oxidative stress, a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof, was not previously diagnosed with blood brain barrier dysregulation or permeability, oxidative stress, a microbleed, systemic inflammation, blood brain barrier inflammation, neuroinflammation, increased level of at least one circulating or CSF cytokine, or a combination thereof, then providing the device for treating and/or preventing one or more effects of the condition.
Steps of the foregoing method and additional methods disclosed herein can be performed in any order. For example, step (b) is performed after step (a) and before step (c). As another example, step (c) is performed after step (a) and before step (b).
As described above under Heading IV, the EDG Receptor Family Modulator, MMP inhibitor, or senolytic agent of the methods of the present technology is provided to the subject by administration.
Devices useful with the methods of the present technology include implantable damping devices of the present disclosure, such as devices comprising a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface formed of a sidewall having one or more at least partially deformable portions configured to move longitudinally and/or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel, and an abating substance disposed within the one or more at least partially deformable portions of the sidewall configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel.
When combined with the implantable damping devices of the present technology, the therapeutic agents described herein are provided at a first dosage that is lower than a second dosage of the same therapeutic agents provided in the absence of the implantable damping devices (e.g., subjects receiving only the therapeutic agents rather than in combination with the implantable damping devices). For example, a subject having a neurodegenerative condition, such as dementia, is provided with a lower dose of Omni-Biotic before, during, or after being provided with the implantable damping device compared to a subject provided with a dose of Omni-Biotic without also being provided with the implantable damping device.
In some embodiments, when combined with the implantable damping devices of the present technology, the therapeutic agents described herein are provided with a first dosing regimen which is less than a second dosing regimen of the same therapeutic agents that is provided in the absence of the implantable damping devices. For example, a subject having a neurodegenerative condition, such as dementia, is provided with a first dosing regimen of Omni-Biotic before, during, or after being provided with the implantable damping device compared to a subject provided with a second dosing regimen of Omni-Biotic without also being provided with the implantable damping device.
In some embodiments, when combined with the implantable damping devices of the present technology, the therapeutic agents described herein are provided with the therapeutic agent by a first route which differs from a second route provided in the absence of the implantable damping devices. For example, a subject having a neurodegenerative condition, such as dementia, is provided with Omni-Biotic by the first route before, during, or after being provided with the implantable damping device compared to a subject provided with Omni-Biotic by the second route without also being provided with the implantable damping device. In some embodiments, the route of administration includes delivering the therapeutic agent to the subject from the device, for example, by eluting the therapeutic agent previously stored in at least a portion of the device.
In addition to the methods, damping devices, and therapeutic agents described herein, the present technology also includes associated systems for treating and/or preventing one or more effects of the subject's condition. Systems of the present technology include an effective amount of at least one therapy for treating and/or preventing one or more effects of the condition and a device for treating and/or preventing one or more effects of the condition. As explained above, devices of the present technology include at least a flexible damping member forming a generally tubular structure having an inner surface formed of a sidewall having one or more at least partially deformable portions, and an abating substance disposed within and configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel. In some embodiments, the therapy includes at least one or more therapeutic agents that may be carried by the damping device. In these embodiments, the therapeutic agent is disposed within and/or carried by at least one or more of the at least partially deformable portions of the damping device. When one or more of the at least partially deformable portions of the damping device are at least partially deformed, the effective amount of the therapeutic agent may be released from the device.
The following examples are illustrative of several embodiments of the present technology. The embodiments described herein are directed to treatment regimens that include a damping device (e.g., any of the devices described above in paragraphs [93] to [136]) and a therapy (e.g., any EDG Receptor Family Modulator to include those discussed above in any of paragraphs [140] to [145]; any MMP inhibitor to include those discussed above in any of paragraphs [146] to [148]; and/or any senolytic agent to include those discussed above in any of paragraphs [149] to [151]). The treatment regimen is not limited to one therapy and may include one or more additional therapies. In accordance with some embodiments, the treatment regimen may be used in methods to treat or prevent a neurological condition using a combination therapy that includes steps of implanting or otherwise providing a damping device (e.g., any of the devices described above in paragraphs [93] to [136]) and administering or otherwise providing a therapy (e.g., any EDG Receptor Family Modulator to include those discussed above in any of paragraphs [140] to [145]; any MMP inhibitor to include those discussed above in any of paragraphs [146] to [148]; and/or any senolytic agent to include those discussed above in any of paragraphs [149] to [151]). In such embodiments, the damping device may be implanted or provided before the therapy, concurrently with the therapy, or after the therapy. One or more additional therapies may also be administered at any time during the combination therapy. Non-limiting examples of the damping device, treatments using the damping device, combination treatments and treatment regimens—as well as studies and models that demonstrate the efficacy, benefits, and advantages of the treatments—are included in the examples below.
Example 1. A device for treating and/or preventing the progression of dementia, comprising:
Example 2. The device of example 1 wherein the damping member is configured to deform in response to a change in blood/pulse pressure or elevated pulse wave intensity/FCWI.
Example 3. The device of example 1 or example 2 wherein, at a location along the damping member coincident with a leading end of a pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.
Example 4. The device of any one of examples 1-3 wherein the lumen of the damping member has an hourglass shape.
Example 5. The device of any one of examples 1˜4 wherein the outer surface is generally cylindrical and the inner surface is undulating.
Example 6. The device of any one of examples 1-5 wherein each of the first and second anchoring members is an expandable stent.
Example 7. The device of any one of examples 1-5 wherein the each of the first and second anchoring members is an expandable mesh.
Example 8. The device of any one of examples 1-5 wherein each of the first and second anchoring members is at least one of an expandable stent and an expandable mesh.
Example 9. The device of any one of examples 1-8 wherein each of the first and second anchoring members is positioned around a circumference of the damping member.
Example 10. The device of any one of examples 1-8 wherein at least a portion of each of the first and second anchoring members is positioned within the damping member and extends through at least a portion of the thickness of the sidewall.
Example 11. The device of any one of examples 1-10 wherein the damping region is a first damping region, and wherein the damping member includes a plurality of damping regions between the first and second end portions.
Example 12. The device of any one of examples 1-11 wherein at least one of the first and second anchoring members comprise a plurality of fixation devices extending radially outwardly from the outer surface of the damping device.
Example 13. The device of any one of examples 1-12 wherein the device is configured to be positioned at a treatment site within the left common carotid artery.
Example 14. The device of any one of examples 1-13 wherein the device is configured to be positioned at a treatment site within the right common carotid artery.
Example 15. The device of any one of examples 1-14 wherein the device is configured to treat Alzheimer's disease.
Example 16. The device of any one of examples 1-15 wherein the device is configured to reduce the occurrence of microbleeds in one or more branches of the artery downstream from the treatment site.
Example 17. A device for treating dementia, comprising:
Example 18. The device of example 17 wherein the damping member is configured to deform in response to a change in blood/pulse pressure or elevated pulse wave intensity/FCWI.
Example 19. The device of example 17 or example 18 wherein, at a location along the damping member coincident with a leading end of a pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.
Example 20. The device of any one of examples 17-19 wherein the lumen of the damping member has an hourglass shape.
Example 21. The device of any one of examples 17-20 wherein the anchoring member is an expandable stent.
Example 22. The device of any one of examples 17-20 wherein the anchoring member is an expandable mesh.
Example 23. The device of any one of examples 17-20 wherein the anchoring member is at least one of an expandable stent and an expandable mesh.
Example 24. The device of any one of examples 17-23 wherein the anchoring member is positioned around a circumference of the damping member.
Example 25. The device of any one of examples 17-23 wherein at least a portion of the anchoring member is positioned within the damping member and extends through at least a portion of the thickness of the sidewall.
Example 26. The device of any one of examples 17-25 wherein the damping region is a first damping region, and wherein the damping member includes a plurality of damping regions between the first and second end portions.
Example 27. The device of any one of examples 17-26 wherein the anchoring member includes a plurality of fixation devices extending radially outwardly from the outer surface of the damping device.
Example 28. The device of any one of examples 17-27 wherein the device is configured to be positioned at a treatment site within the left common carotid artery.
Example 29. The device of any one of examples 17-28 wherein the device is configured to be positioned at a treatment site within the right common carotid artery.
Example 30. The device of any one of examples 17-29 wherein the device is configured to treat Alzheimer's disease.
Example 31. The device of any one of examples 17-29 wherein the device is configured to reduce the occurrence of microbleeds in portions of the blood vessel downstream from the treatment site.
Example 32. A device for treating dementia, comprising:
Example 33. A device for treating a blood vessel, comprising:
Example 34. The device of example 33 wherein the cushioning member is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the vessel, and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the vessel subsequently decreases.
Example 35. A device for treating a blood vessel, comprising:
Example 36. The device of example 35 wherein a portion of the elastically deformable membrane located longitudinally between the proximal and distal anchors defines a region of reduced internal cross-sectional area relative to the proximal and distal anchors when the elastically deformable membrane is radially relaxed.
Example 37. The device of example 35 or example 36 wherein the proximal and distal anchors are each radially expandable between a first diameter before deployment and a second diameter after deployment.
Example 38. The device of any one of examples 35-37, further comprising one or more threads secured to the proximal anchor.
Example 39. The device of example 38 wherein each thread is secured to an eyelet.
Example 40. A device for treating an artery selected from a left common carotid artery, a right common carotid artery, a brachiocephalic artery, the ascending aorta, an internal carotid artery, or an abdominal aorta, the device comprising:
Example 41. The device of example 40 wherein the engagement formation includes sutures and/or staples.
Example 42. The device of example 41 wherein the engagement formation includes a zip lock.
Example 43. A device for treating a left common carotid artery, a right common carotid artery, a brachiocephalic artery, or an ascending aorta, the device comprising:
Example 44. A device for treating and/or preventing the effects of dementia, comprising:
Example 45. The device of example 44 wherein the damping member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.
Example 46. The device of example 44 or example 45 wherein the damping member is configured to be positioned in apposition with an ascending aorta.
Example 47. The device of any one of examples 44-46 wherein the damping member is configured to be positioned in apposition with an inner surface of the blood vessel wall.
Example 48. The device of any one of examples 44-46 wherein the damping member is configured to be positioned in apposition with an outer surface of the blood vessel wall.
Example 49. The device of any one of examples 44-48 wherein the sidewall has an inner diameter, and, when the damping member is in a deployed state, the inner diameter increases then decreases in an axial direction.
Example 50. The device of any one of examples 44-49 wherein the cross-sectional area decreases then increases in longitudinal direction.
Example 51 The device of any one of examples 44-50 wherein the outer surface has a generally cylindrical shape.
Example 52. The device of any one of examples 44-50 wherein the outer surface has an undulating shape.
Example 53. The device of any one of examples 44-52, further comprising an anchoring member coupled to the damping member and axially aligned with only a portion of the damping member, wherein the anchoring member is configured to engage the blood vessel wall and secure the damping member to the blood vessel wall.
Example 54. The device of any one of examples 44-53 wherein the anchoring member is a first anchoring member and the device further comprises a second anchoring member coupled to the damping member, and wherein the second anchoring member:
Example 55. The device of any one of examples 44-54 wherein, when the damping member is positioned adjacent the blood vessel wall, the damping member does not constrain the diameter of the blood vessel wall.
Example 56. A device for treating and/or preventing the effects of dementia, comprising:
Example 57. The device of example 56 wherein the elastic member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.
Example 58. The device of example 56 or example 57 wherein the elastic member is configured to be positioned in apposition with an ascending aorta.
Example 59. The device of any one of examples 56-58 wherein the elastic member is configured to be positioned in apposition with an inner surface of the blood vessel wall.
Example 60. The device of any one of examples 56-58 wherein the elastic member is configured to be positioned in apposition with an outer surface of the blood vessel wall.
Example 61. The device of any one of examples 56-60 wherein the sidewall has an inner diameter, and, when the elastic member is in a deployed state, the inner diameter increases then decreases in an axial direction.
Example 62. The device of any one of examples 56-61 wherein the cross-sectional area decreases then increases in longitudinal direction.
Example 63. The device of any one of examples 56-62 wherein the outer surface has a generally cylindrical shape.
Example 64. The device of any one of examples 56-62 wherein the outer surface has an undulating shape.
Example 65. The device of any one of examples 56-64, further comprising an anchoring member coupled to the elastic member and axially aligned with only a portion of the elastic member, wherein the anchoring member is configured to engage the blood vessel wall and secure the elastic member to the blood vessel wall.
Example 66. The device of example 65 wherein the anchoring member is a first anchoring member and the device further comprises a second anchoring member coupled to the elastic member, and wherein the second anchoring member:
Example 67. The device of any one of examples 56-66 wherein, when the elastic member is positioned adjacent the blood vessel wall, the elastic member does not constrain the diameter of the blood vessel wall.
Example 68. A device for treating and/or preventing the effects of dementia, comprising:
Example 69. The device of example 68, further comprising a structural element coupled to the damping member.
Example 70. The device of example 68 or example 69 wherein, in the deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.
Example 71. The device of any one of examples 68-70 wherein, in the deployed state, the device has a pre-set helical configuration.
Example 72. The device of any one of examples 68-71 wherein the damping member includes a liquid.
Example 73. The device of any one of examples 68-72 wherein the damping member includes a gas.
Example 74. The device of any one of examples 68-73 wherein the damping member includes a gel.
Example 75. The device of any one of examples 68-74 wherein the damping member, in the deployed configuration, is configured to be positioned in apposition with an outer surface of the arterial wall.
Example 76. The device of any one of examples 68-74 wherein the damping member, in the deployed configuration, is configured to be positioned around the arterial wall such that an inner surface of the damping member is in contact with blood flowing through the artery.
Example 77. A device for treating and/or preventing the effects of dementia, comprising:
Example 78. The device of example 77, further comprising a structural element coupled to the damping member.
Example 79. The device of example 77 or example 78 wherein, in the deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.
Example 80. The device of any one of examples 77-79 wherein, in the deployed state, the device has a pre-set helical configuration.
Example 81. The device of any one of examples 77-80 wherein the damping member includes a liquid.
Example 82. The device of any one of examples 77-81 wherein the damping member includes a gas.
Example 83. The device of any one of examples 77-82 wherein the damping member includes a gel.
Example 84. The device of any one of examples 77-83 wherein the damping member, in the deployed configuration, is configured to be positioned in apposition with an outer surface of the arterial wall.
Example 85. The device of any one of examples 77-84 wherein the damping member, in the deployed configuration, is configured to be positioned around the arterial wall such that an inner surface of the damping member is in contact with blood flowing through the artery.
Example 86. A method for treating and/or preventing the effects of dementia, comprising:
Example 87. A method for treating and/or preventing the effects of dementia, comprising:
Example 88. A method for treating at least one of the brachiocephalic artery, the right common carotid artery, the left common carotid artery, the ascending aorta, and the aortic arch, the method comprising:
Example 89. A method of treating a blood vessel, comprising:
Example 90. The method of example 89 wherein transferring the distal anchor includes advancing the distal anchor from the tip of the catheter.
Example 91. The method of example 89 or example 90 wherein transferring the distal anchor includes withdrawing the tip of the catheter whilst the distal anchor remains at a generally constant longitudinal position within the vessel, and exits from the tip of the catheter.
Example 92. The method of any one of examples 89-91 wherein longitudinally positioning the proximal anchor includes applying a first tensile force to one or more threads frangibly secured to the proximal anchor.
Example 93. The method of example 92, further including frangibly rupturing the thread(s) after expanding the proximal anchor by applying a second tensile force which is greater than the first tensile force.
Example 94. The method of example 92, further including disengaging a ring, latch or clasp secured to the thread(s) after expanding the proximal anchor in order to disengage the thread from the proximal anchor.
Example 95. The method of any one of examples 89-94, further including imaging to determine the location of the proximal and/or distal anchors.
Example 96. A method of treating a blood vessel selected from a left common carotid artery, a right common carotid artery or a brachiocephalic artery, a carotid artery, a branch of any of the foregoing, and an ascending aorta, the method comprising:
Example 97. A method for treating dementia, comprising:
Example 98. The method of example 97, further comprising reducing a magnitude of the pulse pressure transmitted to a portion of the blood vessel distal to the damping device.
Example 99. The method of example 98 wherein reducing a magnitude of the pulse pressure includes absorbing a portion of the pulsatile energy of blood flowing through the artery.
Example 100. The method of any one of examples 97-99 wherein changing a contour of the damping member includes increasing an inner diameter of the lumen damping member while an outer diameter of the damping member remains generally constant.
Example 101. The method of any one of examples 97-99 wherein changing a contour of the damping member includes increasing an inner diameter and an outer diameter of the lumen of the damping member.
Example 102. The method of any one of examples 97-99 wherein changing a contour of the damping member includes decreasing a distance between an inner surface of the damping member and an outer surface of the damping member.
Example 103. The method of example 97-102 wherein intravascularly positioning a damping device includes intravascularly positioning a damping device within a left common carotid artery at a treatment site.
Example 104. The method of any one of examples 97-103 wherein intravascularly positioning a damping device includes intravascularly positioning a damping device within a right common carotid artery at a treatment site.
Example 105. The method of any one of examples 97-104 wherein expanding the anchoring member and expanding the damping member occurs simultaneously.
Example 106. The method of any one of examples 97-105 wherein expanding the anchoring member includes expanding the anchoring member with a balloon.
Example 107. The method of any one of examples 97-105 wherein expanding the anchoring member includes withdrawing a sheath to expose the anchoring member to allow the anchoring member to self-expand.
Example 108. The method of any one of examples 97-107 wherein expanding the damping member includes expanding the damping member with a balloon.
Example 109. The method of any one of examples 97-107 wherein expanding the damping member includes withdrawing a sheath to expose the damping member to allow the anchoring member to self-expand.
Example 110. The method of any one of examples 97-109 wherein expanding the anchoring member forces the damping member to expand.
Example 111. The method of any one of examples 97-110 wherein:
Example 112. The method of example 111 wherein the first arterial location is one of a left common carotid artery, a right common carotid artery, an external carotid artery, an internal carotid artery, and an ascending aorta, and the second arterial location is one of a left common carotid artery, a right common carotid artery, an external carotid artery, an internal carotid artery, and an ascending aorta.
Example 113. The method of example 111 wherein the first arterial location is a left common carotid artery and the second arterial location is a right common carotid artery.
Example 114. A method for treating and/or preventing the effects of dementia, comprising:
Example 115. A method for treating and/or preventing the effects of dementia, comprising:
Example 116. A device for treating and/or preventing the progression of dementia, comprising:
Example 117. The device of example 116 wherein the damping member is elastically deformable, and is configured to deform in response to a change in blood/pulse pressure or elevated pulse wave intensity/FCWI.
Example 118. The device of example 116 or example 117 wherein, at a location along the damping member coincident with a leading end of a pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.
Example 119. The device of any one of examples 116-118 wherein the lumen of the damping member has an hourglass shape.
Example 120. The device of any one of example 116-119 wherein the outer surface is generally cylindrical and the inner surface is undulating.
Example 121. The device of any one of examples 116-120 wherein each of the first and second anchoring members is an expandable stent.
Example 122. The device of any one of examples 116-120 wherein the each of the first and second anchoring members is an expandable mesh.
Example 123. The device of any one of examples 116-120 wherein each of the first and second anchoring members is at least one of an expandable stent and an expandable mesh.
Example 124. The device of any one of examples 116-123 wherein each of the first and second anchoring members is positioned around a circumference of the damping member.
Example 125. The device of any one of examples 116-124 wherein at least a portion of each of the first and second anchoring members is positioned within the damping member and extends through at least a portion of the thickness of the sidewall.
Example 126. The device of any one of examples 116-125 wherein the damping region is a first damping region, and wherein the damping member includes a plurality of damping regions between the first and second end portions.
Example 127. The device of any one of examples 116-126 wherein at least one of the first and second anchoring members comprise a plurality of fixation devices extending radially outwardly from the outer surface of the damping device.
Example 128. The device of any one of examples 116-127 wherein the device is configured to be positioned at a treatment site within the left common carotid artery.
Example 129. The device of any one of examples 116-127 wherein the device is configured to be positioned at a treatment site within the right common carotid artery.
Example 130. The device of any one of examples 116-129 wherein the device is configured to treat Alzheimer's disease.
Example 131. The device of any one of examples 116-129 wherein the device is configured to reduce the occurrence of microbleeds in one or more branches of the artery downstream from the treatment site.
Example 132. A device for treating dementia, comprising:
Example 133. The device of example 132 wherein the damping member is elastically deformable, and is configured to deform in response to a change in blood/pulse pressure or elevated pulse wave intensity/FCWI.
Example 134. The device of example 132 or 133 wherein, at a location along the damping member coincident with a leading end of a pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.
Example 135. The device of any one of examples 132-134 wherein the lumen of the damping member has an hourglass shape.
Example 136. The device of any one of examples 132-135 wherein the anchoring member is an expandable stent.
Example 137. The device of any one of examples 132-136 wherein the anchoring member is an expandable mesh.
Example 138. The device of any one of examples 132-137 wherein the anchoring member is at least one of an expandable stent and an expandable mesh.
Example 139. The device of any one of examples 132-138 wherein the anchoring member is positioned around a circumference of the damping member.
Example 140. The device of any one of examples 132-139 wherein at least a portion of the anchoring member is positioned within the damping member and extends through at least a portion of the thickness of the sidewall.
Example 141. The device of any one of examples 132-140 wherein the damping region is a first damping region, and wherein the damping member includes a plurality of damping regions between the first and second end portions.
Example 142. The device of any one of examples 132-141 wherein the anchoring member includes a plurality of fixation devices extending radially outwardly from the outer surface of the damping device.
Example 143. The device of any one of examples 132-142 wherein the device is configured to be positioned at a treatment site within the left common carotid artery.
Example 144. The device of any one of examples 132-142 wherein the device is configured to be positioned at a treatment site within the right common carotid artery.
Example 145. The device of any one of examples 132-144 wherein the device is configured to treat Alzheimer's disease.
Example 146. The device of any one of examples 132-145 wherein the device is configured to reduce the occurrence of microbleeds in portions of the blood vessel downstream from the treatment site.
Example 147. A device for treating dementia, comprising:
Example 148. A device for treating a blood vessel, comprising:
Example 149. The device of example 148 wherein the cushioning member is elastically deformable and is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the vessel subsequently decreases.
Example 150. A device for treating a blood vessel, comprising:
Example 151. The device of example 150 wherein a portion of the elastically deformable membrane located longitudinally between the proximal and distal anchors defines a region of reduced internal cross-sectional area relative to the proximal and distal anchors when the elastically deformable membrane is radially relaxed.
Example 152. The device of example 150 or example 151 wherein the proximal and distal anchors are each radially expandable between a first diameter before deployment and a second diameter after deployment.
Example 153. The device of any one of examples 150-152, further comprising one or more threads secured to the proximal anchor.
Example 154. The device of example 153 wherein each thread is secured to an eyelet.
Example 155. A device for treating an artery selected from a left common carotid artery, a right common carotid artery, a brachiocephalic artery, the ascending aorta, an internal carotid artery, or an abdominal aorta, the device comprising:
Example 156. The device of example 155 wherein, when the wrap is in position around the artery, the wrap entirely or substantially entirely surrounds the artery over a portion of its length.
Example 157. The device of example 155 wherein the engagement formation includes sutures and/or staples.
Example 158. The device of example 155 wherein the engagement formation includes a zip lock.
Example 159. A device for treating a left common carotid artery, a right common carotid artery, a brachiocephalic artery, or an ascending aorta, the device comprising:
Example 160. The device of example 159 wherein the first end of the helical band is secured to the proximal anchor and the second end of the helical band is secured to the distal anchor.
Example 161. A device for treating and/or preventing the effects of dementia, comprising:
Example 162. The device of example 161 wherein the damping member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.
Example 163. The device of example 161 wherein the damping member is configured to be positioned in apposition with an ascending aorta.
Example 164. The device of any one of examples 161-163 wherein the damping member is configured to be positioned in apposition with an inner surface of the blood vessel wall.
Example 165. The device of any one of examples 161-163 wherein the damping member is configured to be positioned in apposition with an outer surface of the blood vessel wall.
Example 166. The device of any one of examples 161-165 wherein the sidewall has an inner diameter, and, when the damping member is in a deployed state, the inner diameter increases then decreases in an axial direction.
Example 167. The device of any one of examples 161-166 wherein the cross-sectional area decreases then increases in longitudinal direction.
Example 168. The device of any one of examples 161-167 wherein the outer surface has a generally cylindrical shape.
Example 169. The device of any one of examples 161-167 wherein the outer surface has an undulating shape.
Example 170. The device of any one of examples 161-169, further comprising an anchoring member coupled to the damping member and axially aligned with only a portion of the damping member, wherein the anchoring member is configured to engage the blood vessel wall and secure the damping member to the blood vessel wall.
Example 171. The device of example 170 wherein the anchoring member is a first anchoring member and the device further comprises a second anchoring member coupled to the damping member, and wherein the second anchoring member:
Example 172. The device of any one of examples 161-171 wherein, when the damping member is positioned adjacent the blood vessel wall, the damping member does not constrain the diameter of the blood vessel wall.
Example 173. A device for treating and/or preventing the effects of dementia, comprising:
Example 174. The device of example 173 wherein the elastic member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.
Example 175. The device of example 173 wherein the elastic member is configured to be positioned in apposition with an ascending aorta.
Example 176. The device of any one of examples 173-175 wherein the elastic member is configured to be positioned in apposition with an inner surface of the blood vessel wall.
Example 177. The device of any one of examples 173-175 wherein the elastic member is configured to be positioned in apposition with an outer surface of the blood vessel wall.
Example 178. The device of any one of examples 173-177 wherein the sidewall has an inner diameter, and, when the elastic member is in a deployed state, the inner diameter increases then decreases in an axial direction.
Example 179. The device of any one of examples 173-178 wherein the cross-sectional area decreases then increases in longitudinal direction.
Example 180. The device of any one of examples 173-179 wherein the outer surface has a generally cylindrical shape.
Example 181. The device of any one of examples 173-179 wherein the outer surface has an undulating shape.
Example 182. The device of any one of examples 173-181, further comprising an anchoring member coupled to the elastic member and axially aligned with only a portion of the elastic member, wherein the anchoring member is configured to engage the blood vessel wall and secure the elastic member to the blood vessel wall.
Example 183. The device of example 182 wherein the anchoring member is a first anchoring member and the device further comprises a second anchoring member coupled to the elastic member, and wherein the second anchoring member:
Example 184. The device of any one of examples 173 to 183 wherein, when the elastic member is positioned adjacent the blood vessel wall, the elastic member does not constrain the diameter of the blood vessel wall.
Example 185. The device of any one of examples 173 to 184 wherein the damping member or elastic member has a low-profile state and a deployed state.
Example 186. The device of example 185 wherein the deployed state is for delivery to a treatment site at a blood vessel wall.
Example 187. The device of example 185 or 186 wherein the damping member or elastic member has a first, lesser outer diameter when in the low-profile state and a second, greater diameter when in the deployed state.
Example 188. A device for treating and/or preventing the effects of dementia, comprising:
Example 189. The device of example 188, wherein the abating substance comprises a quantity of a fluid and/or gel comprising particles, contained within a flexible member, and the particles may move axially relative to the tubular structure within the flexible member.
Example 190. The device of example 189 wherein the flexible member may, at least some locations along the length of the tubular structure, be deformed radially with respect to the tubular structure.
Example 191. The device of any one of examples 188-190, further comprising a structural element coupled to the damping member.
Example 192. The device of any one of examples 188-191 wherein, in a deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.
Example 193. The device of example 192 wherein the damping member includes a break along its length, to allow it to be fitted around the portion of the circumference of the artery.
Example 194. The device of example 193, further comprising cooperating sealing arrangements located on or near opposing edges of the break, to allow the edges to be joined together once the damping member has been fitted around the portion of the circumference of the artery.
Example 195. The device of any one of examples 188-194 wherein, in a deployed state, the device has a pre-set helical configuration.
Example 196. The device of any one of examples 188-195 wherein the damping member includes a liquid.
Example 197. The device of any one of examples 188-196 wherein the damping member includes a gas.
Example 198. The device of any one of examples 188-197 wherein the damping member includes a gel.
Example 199. The device of any one of examples 188-198 wherein the damping member, in a deployed configuration, is configured to be positioned in apposition with an outer surface of the arterial wall.
Example 200. The device of any one of examples 188-199 wherein the damping member, in a deployed configuration, is configured to be positioned around the arterial wall such that an inner surface of the damping member is in contact with blood flowing through the artery.
Example 201. A device for treating and/or preventing the effects of dementia, comprising:
Example 202. The device of example 201 wherein the fluid particles are contained within a flexible member, and the particles may move along the length of the damping member within the flexible member.
Example 203. The device of example 202 wherein the flexible member may, at least some locations along the length of the damping member, be deformed radially with respect to the damping member.
Example 204. The device of any one of examples 201-203, further comprising a structural element coupled to the damping member.
Example 205. The device of any one of examples 201-204 wherein, in the deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.
Example 206. The device of example 205 wherein the damping member includes a break along its length, to allow it to be fitted around the portion of the circumference of the artery.
Example 207. The device of example 206, further comprising cooperating sealing arrangements located on or near opposing edges of the break, to allow the edges to be joined together once the damping member has been fitted around the portion of the circumference of the artery.
Example 208. The device of any one of examples 201-207 wherein, in the deployed state, the device has a pre-set helical configuration.
Example 209. The device of any one of examples 201-208 wherein the damping member includes a liquid.
Example 210. The device of any one of examples 201-209 wherein the damping member includes a gas.
Example 211. The device of any one of examples 201-210 wherein the damping member includes a gel.
Example 212. The device of any one of examples 201-211 wherein the damping member, in the deployed configuration, is configured to be positioned in apposition with an outer surface of the arterial wall.
Example 213. The device of any one of examples 201-212 wherein the damping member, in the deployed configuration, is configured to be positioned around the arterial wall such that an inner surface of the damping member is in contact with blood flowing through the artery.
Example 214. The device of any one of examples 201-213 wherein the damping member has a low-profile configuration and a deployed configuration.
Example 215. A method for treating and/or preventing one or more effects of a condition in a subject in need thereof, the method comprising:
Example 216. The method of example 215, wherein the therapy is an EDG Receptor Family Modulator, an MMP inhibitor, or a senolytic agent or combination thereof.
Example 217. The method of example 216, wherein the EDG Receptor Family Modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.
Example 218. The method of example 216, wherein the MMP inhibitor is doxycycline or dexamethasone.
Example 219. The method of example 216, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.
Example 220. The method of any one of examples 215 to 219, wherein the therapy prevents and/or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and/or reduces expression and/or accumulation of β-amyloid protein in the subject's brain, reduces and/or prevents oxidative stress, reduces and/or prevents ischemia, prevents dysregulation/damage and/or death of a neuron, prevents dysregulation and/or damage to the blood brain barrier, eliminates senescent cells, improves tight junctions, inhibits MMPs, and/or induces transcriptional activation of TIMPs.
Example 221. The method of any one of examples 215 to 220, wherein the therapy is provided at a first dosage which is lower than a second dosage that is provided in the absence of the device.
Example 222. The method of any one of examples 215 to 235, wherein the therapy is provided at a first dosing regimen which is less than a second dosing regimen that is provided in the absence of the device.
Example 223. The method of any one of examples 215 to 236, wherein the therapy is provided via a first route which is different than a second route that is provided in the absence of the device.
Example 224. The method of any one of examples 215 to 235, wherein the therapy is provided by administering the therapy to the subject in need thereof.
Example 225. The method of any one of examples 215 to 222, wherein the condition is neurodegeneration.
Example 226. The method of example 225, wherein neurodegeneration further comprises Alzheimer's disease, dementia, and/or cognitive impairment.
Example 227. The method of any one of examples 215 to 226, wherein the device has a low-profile state and a deployed state, and when in the deployed state, the sidewall is generally tubular.
Example 228. The method of any one of examples 215 to 227, wherein the abating substance is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel subsequently decreases.
Example 229. The method of example 228, wherein when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel, the flexible damping member applies a stress at the first location along a length of the tubular structure.
Example 230. The method of example 229, wherein, after stress is applied at the first location, at least the portion of the abating substance moves longitudinally and/or radially along a length of the tubular structure.
Example 231. The method of example 229, wherein, after stress is applied at the first location, at least a portion of the abating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion to a second location within the first deformable portion of the flexible damping member.
Example 232. The method of example 229, wherein, after stress is applied at the first location, at least the portion of the abating substance is further configured to move longitudinally and/or radially from the first location to a third location within a second deformable portion of the flexible damping member.
Example 233. The method of any one of examples 215 to 232, wherein the inner surface and/or an outer surface has a generally cylindrical shape or an undulating shape that undulates in a longitudinal direction.
Example 234. The method of any one of examples 215 to 233, wherein the flexible damping member is further configured to be positioned around at least a portion of a circumference of a wall of the blood vessel and a pulse wave traveling through the blood vessel applies a stress at a first region of the damping member, at least a portion of the abating substance moves away from the first region to a second region of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 235. The method of any one of examples 215 to 234, wherein the device is further configured to be deployed within a lumen of the blood vessel such that an outer surface of an anchoring member is in apposition with a lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the blood vessel lumen.
Example 236. The method of example 235, wherein when the device is deployed within the blood vessel lumen and a pulse wave traveling through the blood vessel applies a stress at a third location of the damping member, at least a portion of the abating substance moves away from the third location to a fourth location of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 237. A method for treating and/or preventing one or more effects of a condition in a subject in need thereof, the method comprising:
Example 238. The method of example 237, wherein the therapy is EDG Receptor Family Modulator, an MMP inhibitor, or a senolytic agent or combination thereof.
Example 239. The method of example 238, wherein the EDG Receptor Family Modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.
Example 240. The method of example 238, wherein the MMP inhibitor is doxycycline or dexamethasone.
Example 241. The method of example 238, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.
Example 241. The method of any one of examples 237 to 240, wherein the therapy prevents and/or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and/or reduces expression and/or accumulation of β-amyloid protein in the subject's brain, reduces and/or prevents oxidative stress, reduces and/or prevents ischemia, prevents or reduces dysregulation/damage and/or death of a neuron, prevents or reduces blood brain barrier dysregulation or permeability/damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and/or induces transcriptional activation of TIMPs.
Example 242. The method of any one of examples 237 to 241, wherein the therapy is provided at a first dosage which is lower than a second dosage that is provided in the absence of the device.
Example 243. The method of any one of examples 237 to 242, wherein the therapy is provided at a first dosing regimen which is less than a second dosing regimen that is provided in the absence of the device.
Example 244. The method of any one of examples 237 to 243, wherein the therapy is provided via a first route which is different than a second route that is provided in the absence of the device.
Example 245. The method of any one of examples 237 to 244, wherein the therapy is provided by administering the therapy to the subject in need thereof.
Example 246. The method of any one of examples 237 to 244, wherein the condition is neurodegeneration.
Example 247. The method of example 246, wherein neurodegeneration further comprises Alzheimer's disease, dementia, and/or cognitive impairment.
Example 248. The method of any one of examples 237 to 247, wherein the device has a low-profile state and a deployed state, and when in the deployed state, the sidewall is generally tubular.
Example 249. The method of any one of examples 237 to 248, wherein the abating substance is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel subsequently decreases.
Example 250. The method of example 249, wherein when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel, the flexible damping member applies a stress at the first location along a length of the tubular structure.
Example 251. The method of example 250, wherein, after stress is applied at the first location, at least the portion of the abating substance moves longitudinally and/or radially along a length of the tubular structure.
Example 252. The method of example 250, wherein, after stress is applied at the first location, at least a portion of the abating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion to a second location within the first deformable portion of the flexible damping member.
Example 253. The method of example 250, wherein, after stress is applied at the first location, at least the portion of the abating substance is further configured to move longitudinally and/or radially from the first location to a third location within a second deformable portion of the flexible damping member.
Example 254. The method of any one of examples 237 to 253, wherein the inner surface and/or an outer surface has a generally cylindrical shape or an undulating shape that undulates in a longitudinal direction.
Example 255. The method of any one of examples 237 to 254, wherein the flexible damping member is further configured to be positioned around at least a portion of a circumference of a wall of the blood vessel and a pulse wave traveling through the blood vessel applies a stress at a first region of the damping member, at least a portion of the abating substance moves away from the first region to a second region of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 256. The method of any one of examples 237 to 255, wherein the device is further configured to be deployed within a lumen of the blood vessel such that an outer surface of an anchoring member is in apposition with a lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the blood vessel lumen.
Example 257. The method of example 256, wherein when the device is deployed within the blood vessel lumen and a pulse wave traveling through the blood vessel applies a stress at a third location of the damping member, at least a portion of the abating substance moves away from the third location to a fourth location of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 258. A method for treating and/or preventing one or more effects of a condition in a subject in need thereof, the method comprising:
Example 259. The method of example 258, wherein the therapy is an EDG Receptor Family Modulator, an MMP inhibitor, or a senolytic agent or combination thereof.
Example 260. The method of example 259, wherein the EDG Receptor Family Modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.
Example 261. The method of example 260, wherein the MMP inhibitor is doxycycline or dexamethasone.
Example 262. The method of example 260, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.
Example 263. The method of any one of examples 258 to 262, wherein the therapy, prevents and/or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and/or reduces expression and/or accumulation of β-amyloid protein in the subject's brain, decreases inflammation, reduces and/or prevents oxidative stress, reduces and/or prevents ischemia, prevents or reduces dysregulation/damage and/or death of a neuron, prevents or reduces blood brain barrier dysregulation or permeability/damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and/or induces transcriptional activation of TIMPs.
Example 264. The method of any one of examples 258 to 263, wherein the therapy is provided at a first dosage which is lower than a second dosage that is provided in the absence of the device.
Example 265. The method of any one of examples 258 to 264, wherein the therapy is provided at a first dosing regimen which is less than a second dosing regimen that is provided in the absence of the device.
Example 266. The method of any one of examples 258 to 265, wherein the therapy is provided via a first route which is different than a second route that is provided in the absence of the device.
Example 267. The method of any one of examples 258 to 266, wherein the therapy is provided by administering the therapy to the subject in need thereof.
Example 268. The method of any one of examples 258 to 267, wherein the condition is neurodegeneration.
Example 269. The method of example 268, wherein neurodegeneration further comprises Alzheimer's disease, dementia, and/or cognitive impairment.
Example 270. The method of any one of examples 258 to 269, wherein the device has a low-profile state and a deployed state, and when in the deployed state, the sidewall is generally tubular.
Example 271. The method of any one of examples 258 to 270, wherein the abating substance is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel subsequently decreases.
Example 272. The method of example 271, wherein when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel, the flexible damping member applies a stress at the first location along a length of the tubular structure.
Example 273. The method of example 272, wherein, after stress is applied at the first location, at least the portion of the abating substance moves longitudinally and/or radially along a length of the tubular structure.
Example 274. The method of example 273, wherein, after stress is applied at the first location, at least a portion of the abating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion to a second location within the first deformable portion of the flexible damping member.
Example 275. The method of example 274, wherein, after stress is applied at the first location, at least the portion of the abating substance is further configured to move longitudinally and/or radially from the first location to a third location within a second deformable portion of the flexible damping member.
Example 276. The method of any one of examples 258 to 275, wherein the inner surface and/or an outer surface has a generally cylindrical shape or an undulating shape that undulates in a longitudinal direction.
Example 277. The method of any one of examples 258 to 276, wherein the flexible damping member is further configured to be positioned around at least a portion of a circumference of a wall of the blood vessel and a pulse wave traveling through the blood vessel applies a stress at a first region of the damping member, at least a portion of the abating substance moves away from the first region to a second region of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 278. The method of any one of examples 258 to 277, wherein the device is further configured to be deployed within a lumen of the blood vessel such that an outer surface of an anchoring member is in apposition with a lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the blood vessel lumen.
Example 279. The method of example 278, wherein when the device is deployed within the blood vessel lumen and a pulse wave traveling through the blood vessel applies a stress at a third location of the damping member, at least a portion of the abating substance moves away from the third location to a fourth location of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 280. A system for treating and/or preventing one or more effects of a condition in a subject in need thereof, the system comprising:
Example 281. The system of example 280, wherein the EDG Receptor Family Modulator, an MMP inhibitor, or a senolytic agent or combination thereof.
Example 282. The system of example 281, wherein the EDG Receptor Family Modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.
Example 283. The system of example 282, wherein the MMP inhibitor is doxycycline or dexamethasone.
Example 284. The system of example 282, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.
Example 285. The method of any one of examples 280 to 284, wherein the therapy prevents and/or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and/or reduces expression and/or accumulation of β-amyloid protein in the subject's brain, decreases inflammation, reduces and/or prevents oxidative stress, reduces and/or prevents ischemia, prevents or reduces dysregulation/damage and/or death of a neuron, prevents or reduces blood brain barrier dysregulation or permeability/damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and/or induces transcriptional activation of TIMPs.
Example 286. The system of any one of examples 280 to 285, wherein the therapy is provided at a first dosage which is lower than a second dosage that is provided in the absence of the device.
Example 287. The system of any one of examples 280 to 286, wherein the therapy is provided at a first dosing regimen which is less than a second dosing regimen that is provided in the absence of the device.
Example 288. The system of any one of examples 280 to 287, wherein the therapy is provided via a first route which is different than a second route that is provided in the absence of the device.
Example 289. The system of any one of examples 280 to 288, wherein the therapy is provided by administering the therapy to the subject in need thereof.
Example 290. The system of any one of examples 280 to 289, wherein the condition is neurodegeneration.
Example 291. The system of example 290, wherein neurodegeneration further comprises Alzheimer's disease, dementia, and/or cognitive impairment.
Example 292. The system of any one of examples 280 to 291, wherein the inner surface and/or an outer surface has a generally cylindrical shape or an undulating shape that undulates in a longitudinal direction.
Example 293. The system of any one of examples 280 to 292, wherein the device has a low-profile state and a deployed state, and when in the deployed state, the sidewall is generally tubular.
Example 294. The system of any one of examples 280 to 293, wherein the abating substance is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel subsequently decreases.
Example 295. The system of example 294, wherein when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel, the flexible damping member applies a stress at the first location along a length of the tubular structure.
Example 296. The system of example 295, wherein, after stress is applied at the first location, at least the portion of the abating substance moves longitudinally and/or radially along a length of the tubular structure.
Example 297. The system of example 295, wherein, after stress is applied at the first location, at least a portion of the abating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion to a second location within the first deformable portion of the flexible damping member.
Example 298. The system of example 295, wherein, after stress is applied at the first location, at least the portion of the abating substance is further configured to move longitudinally and/or radially from the first location to a third location within a second deformable portion of the flexible damping member.
Example 299. The system of any one of examples 280 to 298, wherein the flexible damping member is further configured to be positioned around at least a portion of a circumference of a wall of the blood vessel and a pulse wave traveling through the blood vessel applies a stress at a first region of the damping member, at least a portion of the abating substance moves away from the first region to a second region of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 300. The system of any one of examples 280 to 299, wherein the device is further configured to be deployed within a lumen of the blood vessel such that an outer surface of an anchoring member is in apposition with a lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the blood vessel lumen.
Example 301. The system of example 300, wherein when the device is deployed within the blood vessel lumen and a pulse wave traveling through the blood vessel applies a stress at a third location of the damping member, at least a portion of the abating substance moves away from the third location to a fourth location of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 302. A system for treating and/or preventing one or more effects of a condition in a subject in need thereof, the system comprising:
Example 303. The system of example 302, wherein the effective amount of the therapy further comprises a first effective amount of the therapy and a second effective amount of the therapy.
Example 304. The system of example 303, wherein the second effective amount of the therapy is greater than the first effective amount of the therapy.
Example 305. The system of example 304, wherein, in response to a first pulsatile blood flow within the blood vessel, the one or more at least partially deformable portions are at least partially deformed to a first degree of deformation.
Example 306. The system of example 305, wherein, in response to a second pulsatile blood flow within the blood vessel, the one or more at least partially deformable portions are at least partially deformed to a second degree of deformation.
Example 307. The system of example 306, wherein the second degree of deformation is greater than the first degree of deformation.
Example 308. The system of example 307, wherein the first effective amount of the therapy is released from the one or more at least partially deformable portions in response to the first degree of deformation.
Example 309. The system of example 308, wherein the second effective amount of the therapy is released from the one or more at least partially deformable portions in response to the second degree of deformation.
Example 310. The system of any one of examples 302 to 309, wherein the therapy is an EDG Receptor Family Modulator, an MMP inhibitor, or a senolytic agent or combination thereof.
Example 311. The system of example 310, wherein the EDG Receptor Family Modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.
Example 312. The system of example 310, wherein the MMP inhibitor is doxycycline or dexamethasone.
Example 313. The system of example 310, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.
Example 314. The method of any one of examples 359 to 384, wherein the therapy prevents and/or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and/or reduces expression and/or accumulation of β-amyloid protein in the subject's brain, decreases inflammation, reduces and/or prevents oxidative stress, reduces and/or prevents ischemia, prevents or reduces dysregulation/damage and/or death of a neuron, prevents or reduces blood brain barrier dysregulation or permeability/damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and/or induces transcriptional activation of TIMPs.
Example 315. The system of any one of examples 359 to 385, wherein the therapy is provided at a first dosage which is lower than a second dosage that is provided in the absence of the device.
Example 316. The system of any one of examples 359 to 386, wherein the therapy is provided at a first dosing regimen which is less than a second dosing regimen that is provided in the absence of the device.
Example 317. The system of any one of examples 359 to 387, wherein the therapy is provided via a first route which is different than a second route that is provided in the absence of the device.
Example 318. The system of any one of examples 359 to 388, wherein the therapy is provided by administering the therapy to the subject in need thereof.
Example 319. The system of any one of examples 359 to 389, wherein the condition is neurodegeneration.
Example 320. The system of example 390, wherein neurodegeneration further comprises Alzheimer's disease, dementia, and/or cognitive impairment.
Example 321. The system of any one of examples 359 to 391, wherein the inner surface and/or an outer surface has a generally cylindrical shape or an undulating shape that undulates in a longitudinal direction.
Example 322. The system of any one of examples 359 to 392, wherein the device has a low-profile state and a deployed state, and when in the deployed state, the sidewall is generally tubular.
Example 323. The system of any one of examples 359 to 393, wherein the abating substance is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel subsequently decreases.
Example 324. The system of example 394, wherein when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel, the flexible damping member applies a stress at the first location along a length of the tubular structure.
Example 325. The system of example 395 wherein, after stress is applied at the first location, at least the portion of the abating substance moves longitudinally and/or radially along a length of the tubular structure.
Example 326. The system of example 395, wherein, after stress is applied at the first location, at least a portion of the abating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion to a second location within the first deformable portion of the flexible damping member.
Example 327. The system of example 395, wherein, after stress is applied at the first location, at least the portion of the abating substance is further configured to move longitudinally and/or radially from the first location to a third location within a second deformable portion of the flexible damping member.
Example 328. The system of any one of examples 359 to 398, wherein the flexible damping member is further configured to be positioned around at least a portion of a circumference of a wall of the blood vessel and a pulse wave traveling through the blood vessel applies a stress at a first region of the damping member, at least a portion of the abating substance moves away from the first region to a second region of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 329. The system of any one of examples 359 to 399, wherein the device is further configured to be deployed within a lumen of the blood vessel such that an outer surface of an anchoring member is in apposition with a lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the blood vessel lumen.
Example 330. The system of example 400, wherein when the device is deployed within the blood vessel lumen and a pulse wave traveling through the blood vessel applies a stress at a third location of the damping member, at least a portion of the abating substance moves away from the third location to a fourth location of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.
Example 331. A method for treating a patient having a condition comprising:
Example 332. The method of example 331, wherein the elevated pulse pressure is a pulse pressure of at least 50 mmHg.
Example 333. The method of example 331 or example 332, wherein the increased level of at least one circulating cytokine in (b) is a level at least about 5% greater than the level in (c).
Example 334. The method of any one of examples 331 to 333, wherein the at least one cytokine is selected from the group consisting of VCAM-1, ICAM-1, TNFα, TGF-β, IL-6, IL-8, IL-1β, IL-12, and NF-κB.
Example 335. The method of example 331, wherein the EDG Receptor Family Modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.
Example 336. The method of example 331, wherein the MMP inhibitor is doxycycline or dexamethasone.
Example 337. The method of example 331, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.
Example 338. The method of any one of examples 331 to 337, wherein the therapy prevents and/or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and/or reduces expression and/or accumulation of β-amyloid protein in the subject's brain, decreases inflammation, reduces and/or prevents oxidative stress, reduces and/or prevents ischemia, prevents or reduces dysfunction/damage and/or death of a neuron, prevents or reduces blood brain barrier dysregulation and/or increase permeability, eliminates senescent cells, improves tight junctions, inhibits MMPs, and/or induces transcriptional activation of TIMPs.
Example 339. The method of any one of examples 331 to 338, wherein the therapy is provided at a first dosage which is lower than a second dosage that is provided in the absence of the device.
Example 340. The method of any one of examples 331 to 339, wherein the therapy is provided at a first dosing regimen which is less than a second dosing regimen that is provided in the absence of the device.
Example 341. The method of any one of examples 331 to 340, wherein the therapy is provided via a first route which is different than a second route that is provided in the absence of the device.
Example 342. The method of any one of examples 331 to 341, wherein the therapy is provided by administering the therapy to the subject in need thereof.
Example 343. The method of any one of examples 331 to 342, wherein step (b) is performed after step (a) and before step (c).
Example 344. The method of any one of examples 331 to 343, wherein step (c) is performed after step (a) and before step (b).
Example 345. The method of any one of examples 331 to 344, wherein the condition is neurodegeneration.
Example 346. The method of example 345, wherein neurodegeneration further comprises Alzheimer's disease, dementia, and/or cognitive impairment.
Example 347. The method of any one of examples 331 to 346, wherein the inner surface and/or an outer surface has a generally cylindrical shape or an undulating shape that undulates in a longitudinal direction.
Example 348. The method of any one of examples 331 to 347, wherein the device has a low-profile state and a deployed state, and when in the deployed state, the sidewall is generally tubular.
Example 349. The method of any one of examples 331 to 348, wherein the abating substance is configured to expand in response to an increase of blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel and relax as the blood/pulse pressure or elevated pulse wave intensity/FCWI within the blood vessel subsequently decreases.
In addition, the following prophetic examples are illustrative of several embodiments of the present technology.
Implantable devices will be positioned at, near, around, within, or in place of at least a portion of a subject's artery in accordance with the present technology. After the implantable devices have been positioned, subjects who received the implantable device will be randomized into one of at least two groups: Group A—placebo, and Group B—therapeutic agent. The placebo will be an experimentally appropriate placebo useful for distinguishing any specific effects of the drug, such as the pharmaceutically acceptable carrier for the active component in the therapeutic agent. The dose of the placebo will be comparable to the amount of pharmaceutically acceptable carrier that subjects in Group B receive. Group B can include two or more subgroups, with subjects being randomly assigned to each subgroup. While the subjects in each of these Group B subgroups each ultimately receive the same therapeutic agent, the dose, route of administration, dosing regimen, or other parameters associated with a therapeutic protocol can be altered.
A therapeutic agent will be delivered to a subject at a pre-specified dose, route of administration, frequency, and duration. After the therapeutic agent has been delivered to the subject, subjects will be randomized into one of at least two groups: Group A—sham, and Group B—implantable device. For those subjects in Group B, implantable devices will be positioned at, near, around, within, or in place of at least a portion of a subject's artery in accordance with the present technology. The sham treatment for Group A includes the delivery methods associated with delivery of the implantable device used for Group B, although the implantable device will not be delivered to the subjects in Group A.
In an alternative study, subjects will be randomized into one of at least two groups: Group A—sham, and Group B—implantable device. For those subjects in Group B, implantable devices will be positioned at, near, around, within, or in place of at least a portion of a subject's artery in accordance with the present technology. The sham treatment for Group A includes the delivery methods associated with delivery of the implantable device used for Group B, although the implantable device will not be delivered to the subjects in Group A. After Groups A and B have been selected and implantable devices (Group B) or sham treatments (Group A) have been provided, a therapeutic agent will be delivered to a subject at a pre-specified dose, route of administration, frequency, and duration.
In another alternative study, subjects will be randomized into one of at least two groups: Group A—sham, and Group B—implantable device. For those subjects in Group B, implantable devices will be positioned at, near, around, within, or in place of at least a portion of a subject's artery in accordance with the present technology, and a therapeutic agent will be delivered to the subjects at a pre-specified dose, route of administration, frequency, and duration at the time of implantation. The sham treatment for Group A includes the delivery methods associated with delivery of the implantable device used for Group B, although the implantable device will not be delivered to the subjects in Group A. Group A will also be delivered a therapeutic agent at a pre-specified dose, route of administration, frequency, and duration at the time of sham treatment.
Influence of Reduced Pulsatility on Agent-Based Therapy: Immortalized human cerebral microvascular endothelial cells, such as HCMEC-SV40 cells, will be cultured and cyclically stretched ˜15%, as described in Gangoda et al, 2018. After the cerebral endothelial cells have been cyclically stretched, confluence will be noted, and samples of conditioned media will be collected. Half of the cerebral endothelial cell cultures will be reduced to ˜5% stretch, while the other half will remain at 15% stretch. This will represent +/−application of the device described herein, respectively.
Next, combination therapy with a drug (MMP inhibitor, (e.g., dexamethasone, doxycycline), S1P modulator (e.g., fingolimod), or senolytic therapy (e.g., D+Q) will be administered as follows:
At a predetermined time after drug dosing, the following assays will be performed for each condition:
In Vivo Model of Device. Male WT mice (e.g., C57Bl/6 and BALB/c) and/or Alzheimer disease model mice will be acclimatized for 2 weeks prior to the experiment. Animals will be kept under a standard condition with room temperature at 21-23° C., 30-70% relative humidity, and a 12:12 h light:dark cycle. Chow and water are available ad libitum.
After 2 weeks of acclimatization, mice will be weighed (weekly throughout the full study). Right carotid and left carotid blood flow and pulse pressure will be measured using any standard method in the art, e.g., a non-invasive Doppler Flow Velocity System (Scintica Instrumentation, Inc.), or invasive pressure catheter (Millar). Mice will then split into groups with comparable average weights. Mice will undergo transverse aortic constriction (TAC) surgery, which involves placing a constriction around the transverse aorta, limiting left ventricular (LV) outflow—thus creating a pressure overload in the LV and inducing an elevated pulse pressure. The TAC surgery will be performed using either (i) a nylon suture to induce a sustained (or permanent) elevated pulse pressure, or (ii) an absorbable suture (e.g., Polyglactin 910, which lasts 14-21 days at maximum strength) to induce a transient (or temporary) elevated pulse pressure, which will gradually dissipate as the suture dissolves, representing the reduction of elevated pulse pressure and associated cerebral microbleeds that occurs over time over time. The specific absorption rate of the selected absorbable suture and its effect on pulse pressure over time in mice will be confirmed. The TAC mice receiving the absorbable suture models the damping device.
Next, the following groups of mice will be examined to confirm that less Alzheimer-related pathology/more blood brain barrier (BBB) integrity is seen in the absorbable suture mice as compared to the nylon suture TAC mice, and to support the damping device's mechanism of action (reducing elevated pulse pressure).
The time point for group comparisons after the TAC procedure may be determined based on when optimal, contrasting pulse pressures are achieved with nylon versus absorbable sutures. In certain aspects, the experiment start point may be approximately 6 weeks post-TAC.
At the time point for group comparisons, mice will be weighed, and blood flow and pulse pressure will be recorded. Mice will then be injected with Evans blue dye (excitation 470/540 nm, emission 680 nm) or any other fluorescent tracer known in the art, undergo perfusion, then sacrificed. Whole brains will be extracted, and brain tissue will immediately be fixed (or snap frozen depending on what the tissue will be used for) and sectioned. Mouse hearts may be collected and weighed. Fixed ipsilateral and contralateral histological brain sections will be stained with Prussian Blue to quantify microbleeds as described in Supplement 1 of Montgolfier et al. (see above) or confocal imaged for fluorescence distribution. Immunohistochemistry or qPCR to measure expression of BBB markers such as tight junction proteins may also be considered as an indicator of BBB integrity. MMP (a marker for increased BBB permeability) and NF-kB (an inflammatory marker associated with Alzheimer's disease) protein expression may also be measured in brain microvessels and brain tissue. Amyloid-beta deposition in neural tissue may be quantified in Alzheimer's model mice as well. Finally, immunohistochemistry of fibrin in brain sections may be conducted to visualize clotting of blood components that have leaked through the BBB into the neuropil.
In Vivo Model of Combination Therapy. Following successful completion of the proof-of-concept experiments described above, the benefit of reducing elevated pulse pressure on the efficacy of drug or cell therapies will be studied in vivo. First, as detailed previously, WT or Alzheimer's model mice will undergo TAC surgery with either a nylon suture or absorbable suture.
At the time point for group comparison after the TAC procedure discussed above, the mice will be dosed (via intracarotid or tail vein) with fluorescently labeled stem/progenitor cells or a drug described herein (e.g., a “therapeutic agent”, “agent”, “therapy”, EDG Receptor Family Modulator, MMP inhibitor, senolytic agent and/or combination thereof).
For Example, the mice may be dosed with a therapeutic agent (MMP inhibitor, (e.g., dexamethasone, doxycycline), S1P modulator (e.g., fingolimod), or senolytic therapy (e.g., D+Q) as shown below:
Exemplary therapies that may be tested according to this example include, but are not limited to, fingolimod, dexamethasone, and doxycycline.
At a time point for group comparisons, mice will be weighed, and blood flow and pulse pressure will be recorded. Mice will then be injected with Evans blue dye/fluorescent tracer, undergo perfusion, then sacrificed. Whole brains will be extracted, and brain tissue will immediately be fixed (or snap frozen depending on what the tissue will be used for) and sectioned. Mouse hearts will be collected and weighed. Fixed ipsilateral and contralateral histological brain sections will be stained with Prussian Blue to quantify microbleeds, see Supplement 1 of Montgolfier et al. (see above), or confocal imaged for fluorescence distribution. The PKH26/CFDA-SE (fluorescence) signal may reveal abundance of recruited fluorescence-labeled stem or progenitor cells in cerebral microvasculature. Evans blue/fluorescent tracer signal may show BBB leakage. Immunohistochemistry or qPCR to measure expression of BBB markers such as tight junction proteins could also be considered as an indicator of BBB integrity. MMP (a marker for increased BBB permeability) and NF-kB (an inflammatory marker associated with Alzheimer's disease and stem cell dysfunction) protein expression could also be measured in brain tissue. Finally, immunohistochemistry of fibrin in brain sections could be conducted to visualize clotting of blood components that have leaked through the BBB into the neuropil.
The in vivo model described herein may be used to test any therapy administered in combination with reduction of elevated pulse pressure (effect of the damping device), including the therapies discussed herein. These combination therapy experiments will confirm whether the absorbable suture TAC mice+therapeutics show less disrupted BBB than the nylon suture TAC mice+therapeutics. If so, this will support the potential for the device to synergistically enhance the efficacy of such therapeutics.
As an alternative to the TAC surgically induced model of elevated pulse pressure discussed above, a chemically induced animal model of elevated pulse pressure may also be used to test biological therapeutics described herein (e.g., a “therapeutic agent”, “agent”, “therapy”, EDG Receptor Family Modulator, an MMP inhibitor, and/or a senolytic agent or combination thereof). Such models can be generated by treating the animals (e.g., rats) with warfarin/vitamin K1 (WVK) in accordance with Essalihi et al., A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment, Am J Hypertens. 2003 February; 16(2): 103-10 (doi: 10.1016/s0895-7061(02)03204-1). The WVK treatment induces isolated systolic hypertension and thus, elevated pulse pressure. This elevated pulse pressure can be reduced with subsequent treatment with darusentan (DAR) and/or acetazolamide (ACTZ) treatment in accordance with Essalihi et al., Regression of medial elastocalcinosis in rat aorta: a new vascular function for carbonic anhydrase, Circulation. 2005 Sep. 13; 112(11):1628-35 (doi: 10.1161/CIRCULATIONAHA, 104.528984).
To compare cerebral vascular health animals experiencing elevated pulse pressure compared to when that pulse pressure is reduced, animals will be treated in one or more of the groups that follow:
After the treatment period, cognition, microbleeds, BBB permeability, neuroinflammation, neurodegeneration, and expression of BBB tight junctions could be quantified and compared for each group of rats detailed in the table above
The study design described herein may be used to test any therapy intended to be administered in combination with reduction of elevated pulse pressure (effect of the damping device), including the therapies described herein. Exemplary therapies treatments that may be tested using this study design include, but are not limited to, fingolimod, dexamethasone, and doxycycline.
This study was performed to investigate a “combined” approach to protecting the Blood Brain Barrier (BBB) by (i) a drug approach, in this case Fingolimod; and (ii) an experimental approach to mimic the effect of a device designed to reduce cerebral pulse pressure. Here, the experimental approach was the application of a resorbable suture to the ascending aorta (TAC procedure) between the right and left common carotid arteries. A permanent TAC produces high pulse pressure in the right cerebral hemisphere, while a transient TAC (resorbable suture) should mimic a period of high pulse pressure followed by normal pulse pressure once the suture is absorbed, similar to that which should be obtained with an External Carotid Artery device, as described in the embodiments herein.
Here, a resorbable TAC suture was used, which the manufacturer represented that would resorb after 7-10 days, however, in all but one mouse, resorption did not occur as discussed below. But, this experiment still gave us the opportunity to test if Fingolimod improved BBB function in the presence of persistently high pulse pressure which is a useful “proof of concept” experiment for the combined drug and device approach.
Study Design. 60 mice were divided evenly into two groups: a permanent TAC group receiving a plain suture, and a transient TAC group receiving a resorbable suture. As shown in
Mortality rate after TAC. The mortality rate of mice in the permanent TAC group (7.4%) was higher than that of the transient TAC group (33.3%). The absorbable suture thread is not as rigid, and it took a few surgeries to adjust the tension applied to the suture.
Body weight follow-up after TAC. As shown in
Echocardiogram Data. Echocardiograms assessing peak velocity were performed before (−3 days) and after (4, 6, 9, 12, 15 and 42 days) TAC surgery in order to detect whether or not the suture was absorbed. As shown in
With the absorbable suture, the variability of the echo cardiac parameters is higher, creating a tendency to a greater impact of TAC on cardiac properties (except for the mean gradient).
Millar data, 6 weeks after TAC. Millar was performed the day of the sacrifice, in untreated and treated (Fingolimod, 0.3 mg/kg/d, during the last 2 weeks of TAC) mice. Carotid arterial and left ventricular pressure parameters are indicated below in Tables 5-6
Cognition (Y Maze—exploratory behaviour). Cognition was measured according to the number of behavior alterations within the three (3) arms of a Y Maze, as shown in
Evan's Blue data. Analyses of the in vivo data above demonstrate that the absorbable suture did not resorb in time, i.e. in 7 to 10 days as advertised by the manufacturer Ethicon, with the exception of mouse 20A. Consequently, there were no statistical differences between the two groups (plain vs. absorbable suture). Likewise, for the other two fingolimod-treatment groups. Nonetheless the mice were treated for the last 2 weeks (starting 4 weeks post-TAC surgery) despite the lack of evidence of normalization of the aorta diameter based on repeated echo assessment, as discussed below.
Twenty three (23) mice were treated with fingolimod (0.01 mg/day in drinking water, i.e. 0.3 mg/kg/d) for the two last weeks, i.e., 4-week TAC post-surgery. In the initial protocol, it was planned to treat the mice after the absorption of the suture estimated at 12 days after the surgery, and thus for 4 and a half weeks. Because absorption of the suture this did not occur, it was decided to treat the mice for the last two weeks even if the damage was expected to be well established.
The images were reconstructed to acquire the whole right hemisphere in order to quantify Evan's blue extravasation. The analysis was performed by a blinded technician using Image J® and background fluorescence filters. Four mice were untreated (23A, 24A, 30A, 40A) and three mice were treated (41A, 42A, 52A).
With computed-generated exclusion of abnormal distribution of individual data of each region-of-interest (ROI) from individual mice, the dot plot shown in
All mice from the two groups (treated and not treated) had the same velocity peak (a proxy of pulse pressure) measured by echocardiography (see
In summary, the S1P1 receptor ligand is likely to be protective by preventing the increase in BBB permeability associated with the rise in cerebrovascular pulse pressure. Additional testing may be performed in a larger cohort of mice, with normalization of cerebrovascular pulse pressure following the absorption of the suture. The treatment would be initiated after only a week of high pulse pressure at the same time of the normalization of the pulse pressure to maximize efficacy.
qPCR analysis. Targeted mRNA expression was performed in the microvascular fraction of the brain. Two approaches were followed: either the quantification (RT-qPCR) was performed in the microvascular fraction of the whole brain (not treated or treated, n=5 per group, unpaired t-test) or after isolation of the ipsi- and contra-lateral hemisphere of the brain of 3 mice treated or not (paired statistical analysis (left vs. right) and unpaired t-test (no TT vs. TT)). The targeted gene transcripts are discussed below.
S1P1 (see
S1P3 (see
B2M (see
CERS4 (see
CERS2 (see
Claudin (see
ICAM-1 (see
VCAM-1 (see
MMP9 (see
Cyclophilin-A (CYPA) has been used as the housekeeping gene. It also known as peptidylprolyl isomerase A (PPIA), which is highly abundant and found in the cytosol.
The S1P1 receptor ligand has complex effects on the brain microcirculation. It has a tendency to decrease S1PR1 and S1PR3 mRNA expression in the ipsilateral hemisphere and globally, respectively; this could represent a downregulation of the receptors in response to the chronic exposure to the agonist. CERS4 expression is decreased in the treated ipsilateral hemisphere, while globally, CERS2 is decreased; again, it seems related to the treatment and the downregulation of the synthesis pathway. More difficult to explain are the following: Claudin-5 expression is globally significantly reduced by the treatment, suggestive of a reduced tight junction between cells. The effect of the treatment on MMP-9 is ambiguous, with a tendency to be increased in the contralateral hemisphere, while ICAM-1 is reduced by the treatment in the ipsilateral hemisphere accompanied by a similar tendency in VCAM-1 expression. Immunofluorescent staining of the brains should provide evidence whether the treatment has protected the ipsilateral hemisphere from the rarefaction in capillaries incurred by the acute and prolonged increase in pulse pressure.
Under a condition of high pulse pressure, Fingolimod appeared to protect the Blood Brain Barrier from excess permeability. Certain cellular analyses (e.g., of Cell Adhesion Molecules) supported the possible benefit of this drug, in this setting. Further experiments may be performed, with optimized “transient TAC” conditions and higher numbers of mice. Taken together, the data are encouraging of a combined approach to BBB protection.
Although many of the embodiments are described above with respect to systems, devices, and methods for treating and/or slowing the progression of vascular and/or age-related neurological conditions (e.g., dementia) via combinatorial therapeutic agents (e.g., drugs) and intravascular methods, the technology is applicable to other applications and/or other approaches, such as surgical implantation of one or more damping devices and/or treatment of blood vessels other than arterial blood vessels supplying blood to the brain, such as the abdominal aorta, in combination with one or more drugs. Any appropriate site within a blood vessel may be treated including, for example, the ascending aorta, the aortic arch, the brachiocephalic artery, the right subclavian artery, the left subclavian artery, the left common carotid artery, the right common carotid artery, the internal and external carotid arteries, and/or branches of any of the foregoing. Moreover, other embodiments in addition to those described herein are within the scope of the technology. Additionally, several other embodiments of the technology can have different configurations, components, or procedures than those described herein. A person of ordinary skill in the art, therefore, will accordingly understand that the technology can have other embodiments with additional elements, or the technology can have other embodiments without several of the features shown and described above with reference to
The above detailed descriptions of embodiments of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include the plural or singular term, respectively. Although specific embodiments of, and examples for, the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative embodiments may perform steps in a different order. The various embodiments described herein may also be combined to provide further embodiments.
Moreover, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and/or additional types of other features are not precluded. It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Further, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.
This application claims priority to U.S. Patent Application No. 63/235,506, entitled “COMBINATORIAL THERAPIES INCLUDING IMPLANTABLE DAMPING DEVICES AND THERAPEUTIC AGENTS FOR TREATING A CONDITION AND ASSOCIATED SYSTEMS AND METHODS OF USE,” filed on Aug. 20, 2021, which is herein incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/AU2022/050928 | 8/19/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63235506 | Aug 2021 | US |
