Patent Application
20220152413
The present disclosure generally relates to the field of systems and methods for manipulating bacterial growth and abundance in biological sample. More particularly, the present invention relates to systems and methods for manipulating gut microbiota.
Over the recent years many efforts have been invested in understanding the link between gut microbiota and health. It was clearly shown that changing the composition of gut resident micro-organisms might have a profound effect on certain health conditions. Based on the scientific evidences accumulated so far and an ongoing research, it seems that the ability to selectively manage the composition of microorganisms in the GI tract, could have an impact of various diseases and be instrumental in treatment. Moreover, it has been demonstrated that adding specific bacteria as food supplement is insufficient. The entire population of micro-organisms inside the GI tract which comprises wide variety of species, which is referred to as gut microbiota, should be taken into consideration, to make an impact. Thus, the ability to control the composition of the gut microbiota, by enriching specific populations of micro-organisms has strong therapeutic potential. Indeed, maintaining biological diversity in the GI tract has been shown beneficial for various food allergies, inflammatory diseases of the GI tract, diabetes and obesity.
Given the diversity of gut microbiota and the complexity of human GI tract as therapeutic target, there is an unmet need in effective, accessible, easy-to-use therapeutic tools for manipulating human gut microbiota.
Accordingly, it is a principal object of the present invention to providing an efficient system and method for manipulating human gut microbiota inside and outside the Gastrointestinal (GI) tract and use of such system as potential therapeutic tool. The invention provides a method for manipulating the growth of a plurality of bacterial species of gut microbiota comprising subjecting the plurality of bacterial species to at least one protocol, wherein said protocol comprises a predefined set of conditions, and, wherein said set of conditions comprises at least one episode of illumination at the wavelength in the range of 400 nm to 900 nm.
The invention further provides a method for obtaining a sample having a desired profile of bacterial species of gut microbiota, the method comprising:
The invention further provides a system for manipulating human gut microbiota in-situ comprising:
The invention yet further provides a method for treating a disorder in a human subject by manipulating gut microbiota, the method comprising:
The invention yet further provides method of fecal transplantation in a subject comprising:
Additional features and advantages of the invention will become apparent from the following drawings and description.
Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description, examples or illustrated in the drawings. The invention is applicable to other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
The invention provides a method for manipulating the growth of a plurality of bacterial species of gut microbiota comprising subjecting the plurality of bacterial species to at least one protocol, wherein said protocol comprises a predefined set of conditions, and, wherein said set of conditions comprises at least one episode of illumination at the wavelength in the range of 400 nm to 900 nm. As used herein, the term “plurality” refers, without limitation to a large number of different types of microorganisms associated with the gut. The term “plurality”, in the context of the invention can be understood as “diversity” of the bacterial species in the gut. The term “gut microbiota” as used herein, is meant to be understood without limitation as a total of micro-organisms residing and/or associated with the GI tract or the gut in healthy and/or diseased state. According to some embodiments, manipulating the growth of the plurality of bacterial species of gut microbiota comprises obtaining a sample of gut microbiota from a subject and, subjecting said sample to the at least one protocol comprising at least one episode of illumination at the wavelength in the range of 400 nm to 900 nm. According to some embodiments, manipulating the growth of the plurality of bacterial species of gut microbiota is done in-situ and comprises subjecting at least a portion of GI tract of a subject to the at least one protocol comprising at least one episode of illumination at the wavelength in the range of 400 nm to 900 nm. The phrase “at least a portion of GI tract” is meant to be understood, without limitation, as a region or a part either small part or a large part, including, without limitation, stomach, small or large intestine of the gastrointestinal tract of the subject. To avoid any doubt, more than one portion of the GI tract can be subjected to the method of the invention. In one embodiment, manipulating the growth of the plurality of bacterial species of gut microbiota is done in-situ and comprises subjecting more than one portion of GI tract of the subject to the at least one protocol comprising at least one episode of illumination at the wavelength in the range of 400 nm to 900 nm. In another embodiment, a single portion of the GI tract is subjected to one or more protocols. In one embodiment, a single portion of the GI tract is repeatedly subjected to a single protocol. In yet another embodiment, a single portion of the GI tract is subjected to multiple protocols. According to some embodiments, a portion and/or portions of the GI tract of the subject may be subjected to one and/or multiple protocols, in any order or any combination suitable to achieve the desired effect. As used herein, the term “manipulating” refers, without limitation, to influencing the composition of bacterial species populations. In one embodiment, the term “manipulating” refers to inhibiting the growth of at least one of the plurality of the bacterial species. In another embodiment, the term “manipulating” refers to eliminating at least one bacterial species in the sample. In yet another embodiment, the term “manipulating” refers to enhancing the growth of at least one bacterial species in the sample. As used herein, the term “protocol” refers, without limitation, to a predetermined set of conditions combination of which is designed to lead to a desired outcome. In one embodiment, the protocol comprises at least one of the following: comprises at least one of the parameters selected from the group consisting of illumination doses, wavelengths, duration of each illumination, number of illumination episodes, frequency of illumination episodes, exposure to oxygen, humidity, exposure to acoustic wave, pH, exposure to radio frequency, temperature, presence of medication, presence of bacterial species, presence of bioactive substance, or any combination thereof. As used herein, the term “bioactive substance” refers, without limitation to signaling molecules, biomolecules; genetic and translation modifying nucleic material; deoxyribonucleic acids (DNA); ribonucleic acids (RNA); organic molecules; inorganic molecules; amino acids; vitamins; polyphenol, steroid, lipophilic poor soluble drug, vasomodulators; peptides; neurotransmitters and analogues of thereof; nucleosides; proteins, including without limitation growth factors, hormones, aptamers, antibodies, cytokines, enzymes, and heat shock proteins; cannabinoid; cannabinoid acid such as tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), cannabinolic acid (CBNa) cannabichromenic acid (CBCa), tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), and cannabichromene (CBC), and endocannobinoids and their analogues, or any other molecules that can exert biological function. As used herein, the term “medication” refers to a substance having a therapeutic effect. As used herein, the term “therapeutic effect” refers, without limitation to response(s) after a treatment of any kind, the results of which are judged to be useful or favorable. This is true whether the result was expected, unexpected, or even an unintended consequence. In one embodiment, the therapeutic effect is selected from the group consisting of anti-inflammatory effect, anti-fibrotic effect, anti-tumor effect, and neuroprotective effect. A non-limiting medicines for combating inflammation, fibrosis, hyperglycolisis, such as diabetic nephropathy, comprises naturally derived ubiquitous phenolic compounds, such as ferulic acid, natural phenols, for example resveratrol, rutin, quercetin, phenolic acids, vitamins, and allicin, cannabinoids selected from the group consisting of tetrahydrocannabinolic acid (THCa), cannabidiolic acid (CBDa), cannabinolic acid (CBNa) cannabichromenic acid (CBCa), tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD) and cannabichromene (CBC) or/and the derivatives of thereof, and synthetic analogues, dexmedetomidine, (α2-AR) agonist, metabolic protectants, including, without limitation, vildagliptin, pristimerin, metformin, pyridoxamine, vasomodulators, epinephrine, rutin, isoxsuprine. The non-limiting list medicines exerting anti-tumor effect comprises, without limitation, chemotherapeutic agent, including without limitation cisplatin, carboplatin, chlorambucil, melphalan, nedaplatin, oxaliplatin, triplatin tetranitrate, satraplatin, imatinib, nilotinib, dasatinib, and radicicol; an immunomodulatory agent, an antiangiogenic agent, a mitotic inhibitor, a nucleoside analog, a DNA intercalating agent, anti-ageing agents, dipeptides, epigenetic factors and modulators, metformin, rapamycin, valproic acid or salt, wortmannin, polyamine spermidine, HDAC inhibitors sodium butyrate, butyric acid, sirtuin activators, resveratrol, co-enzyme CoQ1, small dicarboxylic acids, aspirin, salicylic, benzoic acid, carnitine analogues, human growth hormone, a topoisomerase analogue, an antibody, a cytokine, a folate antimetabolite, anti-glycolisis agent, inhibitor oligonucleotide to a human oncogenic or proto-oncogenic transcription factor, chemotherapeutic agent, an immunomodulatory agent, an antiangiogenic agent, a mitotic inhibitor, a nucleoside analogue, a DNA intercalating agent, a topoisomerase analog, an antibody, a cytokine, or a folate antimetabolite, hexokinase inhibitor, a lactate dehydrogenase inhibitor, a phosphofructokinase 2 or phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibitor, a pyruvate kinase M2 inhibitor, a transketolase inhibitor, a pyruvate dehydrogenase inhibitor, a pyruvate dehydrogenase kinase inhibitor, a glucose-6-phosphate dehydrogenase inhibitor, a GLUT inhibitor, a proton transport inhibitor, a monocarboxylate transporter inhibitor, a hypoxia-inducible factor 1 alpha inhibitor, an AMP-activated protein kinase inhibitor, a glutamine inhibitor, an asparagine inhibitor, an arginine inhibitor, a fatty acid synthase inhibitor, an ATP-citrate lyase inhibitor, dimethyl malate, and malic enzyme 2 inhibitor, or any combination thereof. As used herein, the term “sample of gut microbiota” refers, without limitation to a natural sample originating from GI tract of a human subject. The sample of the invention may be collected directly from the GI tract of the subject or from body waste excreted from the body, such as feces. In one embodiment, the protocol comprises at least one episode of illuminating the sample at the wavelength in the range of 400 nm to 900 nm. In one embodiment, the protocol comprises at least one episode of illuminating the sample at the wavelength in the range of 420 nm to 880 nm. In one embodiment, the wavelength is 420-460 nm; 640-680 nm; and 830-870 nm. According to some embodiments, the wavelength 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 510 nm, 520 nm, 530 nm, 540 nm, 550 nm, 560 nm, 570 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm, 770 nm, 780 nm, 790 nm, 800 nm, 810 nm, 820 nm, 830 nm, 840 nm, 850 nm, 860 nm, 870 nm, 880 nm, 890 nm, and 900 nm. In one embodiment, the protocol comprises at least two illumination episodes. In yet another embodiment, the protocol comprises a sequence of illumination episodes. In another embodiment, similar wavelength is used in each illumination episode. In yet further embodiment, at least two illumination episodes are carried out at different wavelengths. For the sake of clarity, the protocol of the invention may involve as many illumination episodes as needed, at different or identical wavelengths and for the desired duration of time. Any combination of illumination at the indicated wavelengths with other parameters constitute an integral part of the present invention. In one embodiment, the protocol is designed to generate a specific profile of a plurality of bacterial species in the sample. Reference is now made to
In one embodiment, the protocol is designed to enrich at least one microorganism genus in-vitro and/or in-vivo and/or in-situ. As used herein, the term “to enrich” refers, without limitation, to an increase in the proportion of a particular bacterial genus and/or species in the sample. In one embodiment, the protocol is designed to enrich at least one bacterial species. In one embodiment, the protocol is designed to enrich at least one bacterial genus. In one embodiment, the protocol is designed to increase the growth of at least one bacterial species and/or genus and to inhibit the growth of at least one bacterial species and/or genus at the same time. In yet another embodiment, the protocol is designed to increase the growth of more than one bacterial species and/or genii and to inhibit growth of more than one bacterial species and/or genii at the same time. In one embodiment, the protocol is designed to eliminate at least one bacterial species and/or genii. In one embodiment, the protocol is designed to downsize at least one bacterial species and/or genii. In one embodiment, the protocol is designed to obtain a human gut microbiota sample having a desired profile of bacterial species and/or genii. In one embodiment, the protocol. In one embodiment of the invention, the protocol is designed to selectively enhance, reduce or eliminate microorganism species from the sample to obtain a human gut microbiota sample having a desired profile. As used herein, the term “profile” refers, without limitation, to an information relating to characteristics of the sample based on quantification of bacterial species populations constituting the gut microbiota sample.
The invention further provides A method for obtaining a sample having a desired profile of bacterial species of gut microbiota, the method comprising:
In one embodiment, the at least one protocol comprises at least two illumination episodes. In another embodiment, the at least one protocol comprises a sequence of multiple illumination episodes. In one embodiment, the wavelength of illumination is similar in each episode. In one embodiment, the wavelength of illumination is similar in each episode. In one embodiment, the wavelength of illumination is similar in each episode. In another embodiment, the illumination episodes are carried out at least two different wavelengths. In one embodiment, the at least one protocol is designed to enhance the growth of at least one bacterial species population in the starting sample. In another embodiment, the at least one protocol is designed to inhibit the growth of at least one bacterial species population in the starting sample. In another embodiment, the at least one protocol is designed to eliminate the growth of at least one bacterial species population in the starting sample. In one embodiment, the starting sample subjected to at least two protocols. In another embodiment, the at least two protocols are designed to manipulate growth of different bacterial species populations in the starting sample. In one embodiment, the wavelength is 420-460 nm; 640-680 nm; and 830-870 nm. According to some embodiments, the wavelength 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 510 nm, 520 nm, 530 nm, 540 nm, 550 nm, 560 nm, 570 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm, 770 nm, 780 nm, 790 nm, 800 nm, 810 nm, 820 nm, 830 nm, 840 nm, 850 nm, 860 nm, 870 nm, 880 nm, 890 nm, and 900 nm.
In one embodiment, the at least one protocol further comprises at least one of the parameters selected from the group consisting of illumination doses, wavelengths, duration of each illumination, number of illumination episodes, frequency of illumination episodes, exposure to oxygen, humidity, exposure to acoustic wave, pH, exposure to radio frequency, temperature, presence of medication, presence of bacterial species, and presence of bioactive substance.
According to some embodiments, the invention provides a system for manipulating human gut microbiota in-situ comprising:
In one embodiment, the software operated controller is configured to fulfill at least one of the following functions: regulating the function of the light emitting unit, regulating the motion of the vehicle, identifying the location of the vehicle, instructing the vehicle to reach a desired location of the GI tract; delivering the at least one protocol for manipulating the gut microbiota at the desired location, and, actuating release of the cargo from the at least one reservoir at the desired location. comprises a plurality of light emitting elements configured to emit a light at the wavelength in the range of 400 nm to 900 nm. In one embodiment, the light emitting element is a light emitting diode (LED) or a laser beam. In one embodiment, the light emitting element is light emitting diode (LED). According to some embodiments, the system further comprises at least one thermo-electric element in communication with the controller, wherein said thermo-electric element is configured to control local temperature. In one embodiment, the at least one thermo-electric element configured to increase or decrease the local temperature. In another embodiment, the swallowable vehicle comprises at least two thermo-electric elements. In one embodiment the swallowable vehicle of the invention further comprises a second reservoir in communication with the controller and loaded with a liquid media and designed to release the liquid media in a desired location of the GI tract. In one embodiment, release of the liquid media from the second reservoir at the desired location results in a change in humidity. In one embodiment, the liquid media is water or saline. In one embodiment, the reservoir comprises a dispenser.
According to some embodiments, the controller is configured to deliver two or more protocols for manipulating gut microbiota at the desired location. In one embodiment, the two or more protocols are delivered at the same location of the GI tract of the human subject. In yet another embodiment, the two or more protocols are delivered at different locations of the GI tract. In one embodiment, the controller is configured to deliver a plurality of protocols. In one embodiment, the plurality of protocols is delivered at different locations of the GI tract of the subject.
The invention further provides a method for treating a disorder in a human subject by manipulating gut microbiota, the method comprising:
In one embodiment, the swallowable vehicle comprises at least one reservoir configured to carry and release a cargo. In another embodiment, further comprising the step of loading a sample derived from human gut microbiota having a desired profile of bacterial species to the at least one reservoir. In another embodiment, the step of loading the sample derived from gut microbiota to the reservoir precedes step d. In yet another embodiment, the method further comprising the step of releasing the sample derived from human gut microbiota or a portion thereof at the desired location of the GI tract of the subject. In one embodiment, the step of releasing the sample precedes step e. In another embodiment, the step of releasing the sample follows step e. In one embodiment, the protocol comprises multiple illumination episodes. In one embodiment, the software operated controller is configured to fulfill at least one of the following functions: regulating the function of the light emitting unit, regulating the motion of the vehicle, identifying the location of the vehicle, instructing the vehicle to reach a desired location of the GI tract; delivering the at least one protocol for manipulating the gut microbiota at the desired location, and, actuating release of the cargo from the at least one reservoir at the desired location. In yet another embodiment, the protocol further comprises at least one of the parameters selected from the group consisting of illumination doses, wavelengths, duration of each illumination, number of illumination episodes, frequency of illumination episodes, exposure to oxygen, humidity, exposure to acoustic wave, pH, exposure to radio frequency, temperature, presence of medication, presence of bacterial species, and presence of bioactive substance. According to some embodiments, the non-limiting list of disorders of the invention includes: Inflammatory Bowel Diseases, Crohn Disease, Type II Diabetes, HIV, malignancy of GI tract, Ulcerative Colitis, Proctitis, Over-weight, Irritable Bowel syndrome, Alzheimer, depression, Celiac, Specific food allergies, Clostridium Difficile infection, Diarrhea, Chronic constipation, and Dysbiosis.
The invention further provides a method of fecal transplantation in a subject comprising:
As used herein, the term “preparing a fecal sample” refers, without limitation, to subjecting the fecal sample to at least one protocol of the invention to obtain a sample having desired profile of bacterial species. In one embodiment, the method of fecal transplantation further comprises a step of delivery of at least one protocol for manipulating gut microbiota. In one embodiment, the protocol comprises at least one episode of illuminating the GI tract of the subject at the wavelength in the range of 400 nm to 900 nm. In one embodiment, the protocol comprises multiple illuminating episodes. According to one embodiment, the protocol comprises at least one of the parameters selected from the group consisting of illumination doses, wavelengths, duration of each illumination, number of illumination episodes, frequency of illumination episodes, exposure to oxygen, humidity, exposure to acoustic wave, pH, exposure to radio frequency, temperature, presence of medication, presence of bacterial species, presence of bioactive substance, or a combination thereof.
According to some embodiments, the subject is afflicted with a disorder characterized by impaired gut microbiota. A non-limiting list of disorders characterized by impaired gut microbiota includes: Inflammatory Bowel Diseases, Crohn Disease, Type II Diabetes, HIV, malignancy of GI tract, Ulcerative Colitis, Proctitis, Over-weight, Irritable Bowel syndrome, Alzheimer, depression, Celiac, Specific food allergies, Clostridium Difficile infection, Diarrhea, Chronic constipation, and Dysbiosis.
The objective of the study was to test the effect of three different wavelengths of low-level light therapy on fecal microbiota composition in-vitro.
The tested regimens with regard to the Illumination wavelengths and exposure times are detailed in table 2. Illumination was performed in 5 exposures, where in each day, 2 exposures were performed (same time every day, at least 8 hours interval between exposures. i.e. 8:00 am and 16:00 pm) for 2.5 days.
Sample size: 10 fecal samples were tested for each regimen. A total of 40 tested samples+original pre-plated uncultured sample.
Illumination was performed in 5 exposures, where in each day, 2 exposures were performed (same time every day, at least 8 hr. interval between exposures. i.e. 8:00 am and 16:00 pm) for 2.5 days within the anaerobic chamber. After the 5th exposure, a 6-hour duration between illumination and bacterial harvesting is required. Illumination device was held in a specific pre-defined distance from the plate (using a special holder), in order to equally expose all the plate surface.
To isolate the direct effect of the illumination treated fecal microbiota, effects of non-treated and treated fecal microbiota (obtained in experiment 1) on epithelial cells using co-cultures were tested.
Toxigenic strain of C. difficile that expresses both the tcdA and tcdB genes required for the production of toxin A and toxin B: Clostridioides difficile (Prevot) Lawson et al. (ATCC® 43255™) that belongs to toxinotype 0 was used.
C. difficile inhibition was compared to a reference beneficial species such as Bifidobacterium longum that was reported to reduce mucosal inflammation marker in IBD (can be grown on MRS at 37° C. anaerobically)3
C. difficile experiment
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a,” “an” and “the” are intended to include plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements components and/or groups or combinations thereof, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components and/or groups or combinations thereof. As used herein the terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”. The term “consisting of” means “including and limited to”.
As used herein, the term “and/or” includes any and all possible combinations or one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and claims and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.
It will be understood that when an element is referred to as being “on,” “attached” to, “operatively coupled” to, “operatively linked” to, “operatively engaged” with, “connected” to, “coupled” with, “contacting,” etc., another element, it can be directly on, attached to, connected to, operatively coupled to, operatively engaged with, coupled with and/or contacting the other element or intervening elements can also be present. In contrast, when an element is referred to as being “directly contacting” another element, there are no intervening elements present.
It will be understood that, terms such as, for example, “processing”, “computing”, “calculating”, “determining”, “establishing”, “analyzing”, “checking”, or the like, may refer to operation(s) and/or process(es) of a computer, a computing platform, a computing system, or other electronic computing device, that manipulates and/or transforms data represented as physical (e.g., electronic) quantities within the computer's registers and/or memories into other data similarly represented as physical quantities within the computer's registers and/or memories or other information non-transitory storage medium that may store instructions to perform operations and/or processes. It will be understood that, although the terms first, second, etc., may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. Rather, these terms are only used to distinguish one element, component, region, layer and/or section, from another element, component, region, layer and/or section.
Certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention.
Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
Whenever terms “plurality” and “a plurality” are used it is meant to include, for example, “multiple” or “two or more”. The terms “plurality” or “a plurality” may be used throughout the specification to describe two or more components, devices, elements, units, parameters, or the like. The term set when used herein may include one or more items. Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed simultaneously, at the same point in time, or concurrently.
As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
By “patient” or “subject” is meant to include any mammal. A “mammal,” as used herein, refers to any animal classified as a mammal, including but not limited to, humans, experimental animals including monkeys, rats, mice, and guinea pigs, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like.
“Treating” or “treatment” of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
In case of conflict, the patent specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Throughout this application various publications, published patent applications and published patents are referenced.
It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined by the appended claims and includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2020/050239 | 3/3/2020 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62813543 | Mar 2019 | US |
