Patent Application
20220118226
The conventional standard of care for therapeutic and diagnostic interventions for a diseased brain and/or spinal cord of a patient is open surgery.
For example, about 3-5 million people in the United States alone have brain aneurysms, and about 30-40 percent of aneurysms are treated with open surgery. In addition, about 80,000 new brain tumors are diagnosed each year, with surgery and systemic chemotherapy/radiation being the typical treatment.
There has been hesitation to use catheters in the spinal canal subarachnoid space of a patient having a diseased brain and/or spinal cord because of potential injury to the spinal cord.
In one aspect, a minimally-invasive access and delivery medical device is provided for therapeutic and/or diagnostic interventions within the subarachnoid space of a patient. The medical device includes an elongate, flexible microcatheter having proximal and distal ends, a guidewire extending through the microcatheter along which the microcatheter may be advanced or retracted, and a fiber-optic probe extending through the microcatheter from the distal to the proximal end of the microcatheter. The fiber-optic probe has a tip extending adjacent the distal end of the microcatheter such that the tip provides an end viewing face directed and/or adjustably directed in a direction toward the guidewire. A camera is connected to the fiber-optic probe adjacent the proximal end of the microcatheter to provide real-time visualization of the contents of the subarachnoid space of the patient and guidewire during navigation of the distal end of the microcatheter via the guidewire to the brain of the patient.
According to another aspect, the medical device may also include a steering wire extending through the microcatheter from the proximal to the distal end of the microcatheter. The steering wire may be fixed to the distal end to enable steering of the distal end of the microcatheter.
According to a further aspect, a method of accessing and providing a path of delivery to the subarachnoid space of a patient for therapeutic and/or diagnostic interventions is provided. The method includes the steps of inserting a distal end of an elongate, flexible microcatheter into the subarachnoid space of the patient and navigating the distal end of the microcatheter within the patient to other locations within the subarachnoid space. For instance, the microcatheter may be inserted through a puncture and navigated within the spinal canal of the patient. The microcatheter includes a guidewire that extends from a proximal end through a distal end of the microcatheter along which the microcatheter may be advanced or retracted during the inserting and navigating steps. The microcatheter may or may not further include a steering wire that extends through the microcatheter from the proximal end to the distal end of the microcatheter. For instance, the steering wire, if present, may be fixed to the distal end to enable steering of the distal end of the microcatheter during the navigating step. The microcatheter further includes a fiber-optic probe extending through the microcatheter from the distal end to the proximal end of the microcatheter. The fiber-optic probe has a tip extending adjacent the distal end of the microcatheter such that the tip provides an end viewing face that is directed or adjustably directed in a direction toward the guidewire. The microcatheter additionally includes a camera connected to the fiber-optic probe adjacent the proximal end of the microcatheter such that real-time visualization of the contents of the subarachnoid space and the guidewire via the end viewing face of the fiber-optic probe is provided during the navigating step.
Other aspects of the invention will be readily apparent from the following detailed description.
The following definitions are provided. It is to be noted that the term “a” or “an” refers to one or more. As such, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein.
The words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively. The words “consist”, “consisting”, and its variants, are to be interpreted exclusively, rather than inclusively. While various embodiments in the specification are presented using “comprising” language, under other circumstances, a related embodiment is also intended to be interpreted and described using “consisting of” or “consisting essentially of” language.
As used herein, the term “about” means a variability of 10% from the reference given, unless otherwise specified.
A “patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla. In one embodiment, the patient is a human.
The “subarachnoid space” is the space between the arachnoid membrane and pia mater that covers the central nervous system, surrounds the brain and spinal cord, and contains cerebrospinal fluid.
The term “real-time visualization” refers to viewing images within milliseconds of the images actually being taken so that it is available virtually immediately as feedback.
Unless otherwise specified, the term “central nervous system” includes the brain, the spinal cord, and the spinal nerves and their components within the subarachnoid space (spinal ganglia). In certain embodiments, the brain will be the specific target of treatment and the other parts of the central nervous system will not be targeted for therapy.
As used herein, the term “peripheral nervous system” refers to nerves and ganglia outside the brain and spinal cord.
Unless defined otherwise in this specification, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art and by reference to published texts, which provide one skilled in the art with a general guide to many of the terms used in the present application.
Embodiments of a medical device are disclosed herein which enable therapeutic and diagnostic interventions in the subarachnoid space of a patient in a minimally-invasive manner. The medical device may be provided in the form of a microcatheter which may be inserted into the subarachnoid space by a small puncture, such as a lumbar puncture in the lower back of the patient, and then navigated within the subarachnoid space through cerebrospinal fluid, such as along the spinal canal toward the cisterna magna at the base of the patient's brain or any other location within the subarachnoid space. The microcatheter may include a guidewire, a steering wire or wires, a fiber-optic lighting element, and a fiber-optic probe or other micro-camera that enables the contents of the subarachnoid space within cerebrospinal fluid (CSF), which is typically clear, to be viewed in real-time as the microcatheter is navigated within the subarachnoid space.
Embodiments of the above referenced minimally-invasive access and therapy delivery system reduce morbidities and cost associated with open surgery. In addition, this approach allows for patients to be treated in fluoroscopy suites (outside of an operating room) thereby greatly lowering the cost of such procedures. Patients should also have faster recovery times, since the access site may be in the lumbar spine and only a bandage or suture would be needed for wound care, entirely eliminating the need to recover from a craniotomy.
By way of example, and not be way of limitation, the above referenced minimally-invasive access and therapy delivery system could be used for delivery of gene therapy, drug delivery (e.g. direct treatment of brain for epilepsy, brain tumors, etc.), probes, laser ablation, medical tools such as a lasso or electrode, and the like to a diseased brain. In addition, the system could be used for other applications, such as: electrical ablation probe; electrical probe; Ph sensor; gastrointestinal (GI) imaging (replaces capsule); lasso for aneurysm; thermal ablation; cryotherapy; scar tissue removal (fertility); bladder access and imaging; lung access and imaging; radiation emitting probe; lymphatic imaging and access; egg harvesting; and the like.
According to one embodiment, the above referenced minimally-invasive access and therapy delivery system is used to access the subarachnoid space for delivering novel gene therapies to treat a variety of congenital and other diseases. Novel gene therapies are being developed to treat a variety of diseases, and circumventing the blood brain barrier is essential for these therapies to be effective (i.e., central nervous system gene therapy vectors may need to be placed directly into the cisterna magna (at the skull base) for greater transmission). Such a delivery system, which bypasses the blood brain barrier, may reduce the amount (e.g., volume and/or dose) of costly gene therapy required. In certain embodiments, the devices provided herein may improve transduction 10-fold to 100-fold compared to regular lumbar delivery of gene therapy.
According to other embodiments, the system may be used in a procedure to fix an aneurysm. For instance, the system may be used to place electrodes directly on the brain to find an epileptic focus or may be used to have brain tumors treated with laser ablation. In addition, the system may be used for direct infusion of chemotherapy and catheter directed tumor ablation. Of course, these are only a few examples of the benefits of a dedicated intrathecal treatment system according to embodiments disclosed herein.
According to one embodiment, a microcatheter 10 is provided having a distal end 12 as shown in
One or more steering wires, 18 and 20, may extend from the proximal end 16 to the distal end 12 within the microcatheter 10. In the embodiment shown in
The steering wire or wires, 18 and 20, may be secured to the distal end 12 and a force applied to the steering wires at the proximal end 16 of the microcatheter 10 may be used to direct the distal end 12 in one direction or the other to enable safe navigation within the subarachnoid space. For instance, navigation may take place within the spinal canal of a patient, such as from a lumbar puncture to the cisterna magna. Of course, the microcatheter may be navigated to other locations within the subarachnoid space or within other spaces. In addition, the steering wire may permit the distal end 12 to form a relatively tight bend or curve, for instance of about 180° as best shown in the radiographic images of
In one contemplated embodiment, one of the steering wires may be replaced with a fiber-optic light transmission element or the like (not shown) for permitting light to be projected from the distal end of the microcatheter.
A fiber-optic or like probe 22 also extends from the proximal end 16 to the distal end 12 within the microcatheter 10. As best shown in
According to the embodiment illustrated in
As best shown in
A multi-lumen protective tubing 30 forming the distal end 14 may extend from the tubing 28. As best shown in
According to an embodiment, the tubing 30 that forms the distal end may be more or less easily flexed by the steering wires than the tubing 28. Thus, the microcatheter may have varying degrees of flexibility/stiffness throughout its length. For instance, as best shown in
By way of example, and not by way of limitation, the tubing 28 and 30 may be of a size of less than 5 French (Fr), 3.5 Fr or less, or 3 Fr or less. These sizes correspond to outer diameters of less than 1.66 mm (0.07 inch), 1.167 mm (0.046 inch) or less, and 1 mm (0.039 inch) or less. For instance, as shown in
Further, as shown in
The proximal end 16 of the microcatheter 10 is shown in
The handle body 32 includes a control lever 40 or the like which may be used to steer the distal end 14 of the microcatheter 10. For instance, by toggling the control lever 40 in a given direction the control lever 40 may cause a pulling force to be applied to a steering wire, 18 or 20, so that the distal end 14 is steered, advanced, and/or curved in a particular direction. Thus, in use, an operator views the images captured at the distal end in real-time and controls the direction of the distal end 14 of the microcatheter 10 to navigate the subarachnoid space.
Although not illustrated, a light source (not shown) may also be housed within the caddy 34 and a fiber-optic cable (not shown) may extend through the handle body 32 to the distal end 14 through with light may be projected.
According to an embodiment, a method of accessing and providing a path of delivery to the subarachnoid space of a patient includes the steps of extending the distal end of the above referenced elongate, flexible, multi-lumen microcatheter through a puncture into the subarachnoid space of the patient and navigating the distal end of the microcatheter within the spinal canal of the patient to other locations within the subarachnoid space of the patient. The method may include a step of delivering at least one of gene therapy, a drug, a probe, a medical tool, laser ablation, an electrode, and a lasso to the distal end of the microcatheter. The method may also include a step of steering the distal end of the microcatheter during the navigating step by toggling a control lever on a handle at the proximal end of the microcatheter. The method may further include the step of projecting light from the distal end of the microcatheter with a fiber-optic light element extending through the microcatheter.
According to another embodiment, a method of accessing and providing a path of delivery to the subarachnoid space of a patient includes the steps of extending the distal end of the above referenced elongate, flexible, microcatheter through a puncture in the cisterna magna. For gene therapy, navigating to the cisterna magna from lumbar puncture may be adequate; however, for some other therapies, it may be advantageous to navigate from the cisterna magna to the surface of the brain (i.e., epilepsy treatment).
The device provided herein minimizes the risk associated with current devices used for delivery of intrathecal therapies and surgical procedures for the brain or other parts of the central nervous system. In particular, use of the device provided herein avoids the risk associated with prior art devices used for intrathecal, and particularly, intracerebroventricular injection.
In certain embodiments, the device may be used for delivering a therapeutic or other regimen to the central nervous system of a patient in need thereof. Examples of such therapies include, e.g., oncolytic therapy, gene therapy, anti sense therapy, immunotherapy, delivery of small molecule drugs, delivery of anesthesia, pain medication, or chemotherapies. Additionally, the device may be used for treatments of aneurysms and/or vascular diseases of the brain and spine, including, without limitation arteriovenous malformations, fistulas, cavernomas, among other conditions. This device may be useful in treating patients with a variety of indications including, without limitation, primary or metastatic cancers of the brain and/or central nervous system, lysosomal storage diseases, movement disorders including but not limited to primary essential tremor, Parkinson's Disease, Alzheimer's Disease, mucopolysaccharidoses (MPS) which include seven sub-types: MPS I, MPS II, MPS III, MPS IV, MPS VI, MPS VII, and MPS IX; spinal muscular atrophy (SMA), Batten disease (neuronal ceroid lipofuscinoses, or NCLs); transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jacob disease), amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington disease, Canavan's disease, traumatic brain injury, spinal cord injury, migraine, lysosomal storage diseases, stroke, and infectious disease affecting the central nervous system. Examples of suitable gene therapy and immunotherapy gene products and antibodies are identified, e.g., in WO 2017/075119.
As used herein, the “subject” or “patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.
Optionally, the device is useful for delivery of an active drug(s) which is in a pharmaceutically acceptable suspension or solution (e.g., an aqueous based composition), which optionally contains conventional pharmaceutical ingredients, such as preservatives, or chemical stabilizers.
Suitably, the composition may contain water (e.g., saline), a surfactant, and a physiologically compatible salt or mixture of salts. Suitably, the formulation is adjusted to a physiologically acceptable pH, e.g., in the range of pH 6 to 9, or pH 6.5 to 7.5, pH 7.0 to 7.7, or pH 7.2 to 7.8. As the pH of the cerebrospinal fluid is about 7.28 to about 7.32, for intrathecal delivery, a pH within this range may be desired. However, other pHs within the broadest ranges and these subranges may be selected for other route of delivery.
A suitable surfactant, or combination of surfactants, may be selected from among nonionic surfactants that are nontoxic. In one embodiment, a difunctional block copolymer surfactant terminating in primary hydroxyl groups is selected, e.g., such as Pluronic® F68 [BASF], also known as Poloxamer 188, which has a neutral pH, has an average molecular weight of 8400. Other surfactants and other Poloxamers may be selected, i.e., nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol. In one embodiment, the formulation contains a poloxamer. These copolymers are commonly named with the letter “P” (for poloxamer) followed by three digits: the first two digits×100 give the approximate molecular mass of the polyoxypropylene core, and the last digit×10 gives the percentage polyoxyethylene content. In one embodiment Poloxamer 188 is selected. The surfactant may be present in an amount up to about 0.0005% to about 0.001% of the suspension.
In one example, the formulation may contain, e.g., buffered saline solution comprising one or more of sodium chloride, sodium bicarbonate, dextrose, magnesium sulfate (e.g., magnesium sulfate .7H2O), potassium chloride, calcium chloride (e.g., calcium chloride .2H2O), dibasic sodium phosphate, and mixtures thereof, in water. Suitably, for intrathecal delivery, the osmolarity is within a range compatible with cerebrospinal fluid (e.g., about 275 to about 290); see, e.g., emedicine.medscape.com/-article/2093316-overview. Optionally, for intrathecal delivery, a commercially available diluent may be used as a suspending agent, or in combination with another suspending agent and other optional excipients. See, e.g., Elliotts B® solution [Lukare Medical]. The pH of Elliotts B Solution is 6 to 7.5, and the osmolarity is 288 mOsmol per liter (calculated). In certain embodiments, the composition containing the rAAVhu68.SMN1 gene is delivered at a pH in the range of 6.8 to 8, or 7.2 to 7.8, or 7.5 to 8. For intrathecal delivery, a pH above 7.5 may be desired, e.g., 7.5 to 8, or 7.8.
In certain embodiments, the formulation may contain a buffered saline aqueous solution not comprising sodium bicarbonate. Such a formulation may contain a buffered saline aqueous solution comprising one or more of sodium phosphate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and mixtures thereof, in water, such as a Harvard's buffer. The aqueous solution may further contain Kolliphor® P188, a poloxamer which is commercially available from BASF which was formerly sold under the trade name Lutrol® F68. The aqueous solution may have a pH of 7.2.
In another embodiment, the formulation may contain a buffered saline aqueous solution comprising 1 mM Sodium Phosphate (Na3PO4), 150 mM sodium chloride (NaCl), 3 mM potassium chloride (KCl), 1.4 mM calcium chloride (CaCl2), 0.8 mM magnesium chloride (MgCl2), and 0.001% Kolliphor® 188. See, e.g., harvardapparatus.com/harvard-apparatus-perfusion-fluid.html. In certain embodiments, Harvard's buffer is preferred due to better pH stability observed with Harvard's buffer.
In certain embodiments, the device provided herein avoids the need for one or more permeation enhancers. Examples of suitable permeation enhancers may include, e.g., mannitol, sodium glycocholate, sodium taurocholate, sodium deoxycholate, sodium salicylate, sodium caprylate, sodium caprate, sodium lauryl sulfate, polyoxyethylene-9-laurel ether, or EDTA. In another embodiment, a composition may include includes a carrier, diluent, excipient and/or adjuvant. Suitable carriers may be readily selected by one of skill in the art in view of the indication for which the transfer virus is directed. For example, one suitable carrier includes saline, which may be formulated with a variety of buffering solutions (e.g., phosphate buffered saline). Other exemplary carriers include sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil, sesame oil, and water. The buffer/carrier should include a component that prevents the rAAV, from sticking to the infusion tubing but does not interfere with the rAAV binding activity in vivo.
Suitable exemplary preservatives include chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin, glycerin, phenol, and parachlorophenol. Suitable chemical stabilizers include gelatin and albumin.
In certain embodiments, a suitable volume (e.g., 1 cc-5 cc) of cerebrospinal fluid (CSF) is withdrawn prior to delivery of a selected suspension or solution to a patient. In certain embodiments, the volume of suspension or solution withdrawn from the CSF corresponds to the volume being delivered to the patient via the device. In certain embodiments, this may be done following lumbar puncture and/or following insertion of the device. Intravenous (IV) contrast may be administered prior to or during insertion of the device. The patient may be anesthetized, intubated, and positioned on the procedure table.
Suitable volumes for delivery of these doses and concentrations may be determined by one of skill in the art. For example, volumes of about 1 μL to 150 mL may be selected, with the higher volumes being selected for adults. Typically, for newborn infants a suitable volume is about 0.5 mL to about 10 mL, for older infants, about 0.5 mL to about 15 mL may be selected. For toddlers, a volume of about 0.5 mL to about 20 mL may be selected. For children, volumes of up to about 30 mL may be selected. For pre-teens and teens, volumes up to about 50 mL may be selected. In still other embodiments, a patient may receive an intrathecal administration in a volume of about 5 mL to about 15 mL are selected, or about 7.5 mL to about 10 mL. Other suitable volumes and dosages may be determined. The dosage will be adjusted to balance the therapeutic benefit against any side effects and such dosages may vary depending upon the therapeutic application for which the recombinant vector is employed.
In certain embodiments, a gene therapy vector is an AAV-based vector having a dose of about 1×109 GC/g brain mass to about 1×1012 GC/g brain mass. In certain embodiments, the dose may be in the range of about 3×1010 GC/g brain mass to about 3×1011 GC/g brain mass. In certain embodiments, the dose may be in the range of about 5×1010 GC/g brain mass to about 1.85×1011 GC/g brain mass. In one embodiment, the vector may be delivered in doses of from at least about least 1×109 GCs to about 1×1015, or about 1×1011 to 5×1013 GC. Still other suitable doses of gene therapy vectors or non-vector delivery systems may be readily selected by one of skill in the art.
Similarly, other compositions may be delivered via the device for treatment of various central nervous system injuries, diseases, conditions or disorders.
All publications cited in this specification, including those specifically recited below, are incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2020/014402 | 1/21/2020 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62795350 | Jan 2019 | US |
