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WO2021207466A1 - Diagnostic et traitement de la fibromyalgie - Google Patents

Diagnostic et traitement de la fibromyalgie Download PDF

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Publication number
WO2021207466A1
WO2021207466A1 PCT/US2021/026340 US2021026340W WO2021207466A1 WO 2021207466 A1 WO2021207466 A1 WO 2021207466A1 US 2021026340 W US2021026340 W US 2021026340W WO 2021207466 A1 WO2021207466 A1 WO 2021207466A1
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Prior art keywords
fibromyalgia
antibody
autoimmune
subject
syndrome
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PCT/US2021/026340
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English (en)
Inventor
Ethan Russo
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Credo Science LLC
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Credo Science LLC
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/948—Sedatives, e.g. cannabinoids, barbiturates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2842—Pain, e.g. neuropathic pain, psychogenic pain

Definitions

  • the invention relates to diagnosing and treating autoimmune disorders such as fibromyalgia. Some embodiments of the invention relate to methods, systems, assays and kits for diagnosing the autoimmune disorder such as fibromyalgia. The invention also relates to methods, systems and assays for determining treatments for fibromyalgia, for example, an assay for determining effective compositions and dosages.
  • Fibromyalgia was likely first described by Sir William Gowers as fibrositis in the early 1900s, a condition characterized as soft tissue pain that could wander in the body, and which was aggravated by overuse. In the 1980s, fibromyalgia became the preferred term due to a failure to identify inflammation or other objective changes in tissue biopsies from affected patients.
  • Formal diagnostic parameters Wang F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010;62(5):600-10.
  • Fibromyalgia is noteworthy for its characteristic painful nodules dubbed as trigger points that are particularly prevalent in the shoulder and neck that are frequently of sufficient severity to limit physical activity.
  • the disorder has a clear association with depression and anxiety, but debate surrounds the timing and relationship of these comorbidities. Like migraine, it is more prevalent in women and invariably disrupts sleep. The disorder remains controversial in some quarters, but it is nonetheless the most common diagnosis in American rheumatology practices. Many authorities now posit a central sensitization consistent with neuropathic pain at the root of the syndrome.
  • fibromyalgia like migraine, was associated with secondary hyperalgesia, that is, a lowered threshold to pain in areas adjacent to the primarily affected parts, for which the authors suggested pharmacological NMD A blockade for what they interpreted as a deficit in serotonergic analgesia (further information can be found in Russo EB.
  • Fibromyalgia has been hypothesized to relate to a “clinical endocannabinoid deficiency” that could be linked to a genetic susceptibility or be an acquired disorder after injury.
  • the invention relates to the finding that fibromyalgia and other disorders with unexplained etiology are autoimmune manifestations in which the points of attack are cannabinoid receptors (CB1 or CB2).
  • CBD1 or CB2 cannabinoid receptors
  • This can be analogous to similar pathophysiologic mechanisms related to autoimmune conditions affecting other receptor systems, e.g., acetylcholine receptors in myasthenia gravis and the NMDA receptor in anti-NMDA receptor encephalitis. Further information can be found in Russo E. B. (2004).
  • Clinical endocannabinoid deficiency can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro endocrinology letters, 25(1-2), 31-39; and Russo E. B. (2016). Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Cannabis and cannabinoid research, 1(1), 154-165; the entireties of which are hereby incorporated by reference herein for all purposes.
  • Embodiments of the invention relate to a method for diagnosing or monitoring a subject for fibromyalgia including providing a biological sample from a subject; detecting a presence of an anti-CBl or an anti-CB2 antibody in the biological sample with an assay; and determining a presence or likely presence of fibromyalgia if the presence of anti-CBl or anti-CB2 antibody is detected.
  • Other embodiments of the invention relate to a method of treating fibromyalgia including administering a composition that inhibits an anti-CBl or anti-CB2 antibody to a subject with fibromyalgia.
  • synthesized anti-auto-antibodies can be administered as a treatment for the disorder.
  • the composition is identified by the assay used for diagnosing or monitoring a subject for fibromyalgia.
  • Some embodiments of the invention relate to a method for diagnosing or monitoring a subject for fibromyalgia.
  • the method can include providing a biological sample from a subject and detecting the presence of an anti-CB 1 or an anti-CB2 antibody in the biological sample with an assay.
  • the presence of an anti-CB 1 or an anti-CB2 antibody can be indicative of a presence or likely presence of fibromyalgia in the patient.
  • Some embodiments of the invention relate to a method for diagnosing or monitoring a subject for fibromyalgia that can include providing a biological sample from a subject and detecting a level of anti-CB 1 or anti-CB2 antibodies in the biological sample with an assay.
  • a significantly higher level of anti-CB 1 or an anti-CB2 antibodies compared to a level in a control sample can be indicative of a presence or likely presence of fibromyalgia in the patient.
  • the sample can be serum.
  • the assay can be an ELISA.
  • Some embodiments of the invention relate to a system for diagnosing or monitoring a subject for fibromyalgia using a method disclosed herein.
  • the system can include an immunoassay.
  • the system further includes a computer.
  • kits for diagnosing or monitoring a subject for fibromyalgia using a method disclosed herein can include reagents for an immunoassay.
  • Some embodiments of the invention relate to a method of determining a therapy for fibromyalgia for a subject in need thereof.
  • the method can include measuring a binding affinity of a composition to CB 1 or CB2 and selecting a composition with a higher binding affinity to CB1 compared to an anti-CBl autoimmune antibody or a higher binding affinity to CB2 compared to an anti-CB2 autoimmune antibody, or both.
  • Some embodiments of the invention relate to a method of treating fibromyalgia that can include administering the composition selected in the method disclosed above that inhibits an anti-CB 1 or anti-CB2 antibody to a subject with fibromyalgia.
  • the method can further include administration of a prebiotic or a probiotic or both.
  • Methods for diagnosing and treating autoimmune disorders such as fibromyalgia are provided. Some embodiments of the invention relate to methods, systems, assays and kits for diagnosing the autoimmune disorder such as fibromyalgia. The disclosure also provides methods, systems and assays for determining treatments for fibromyalgia, for example, an assay for determining effective compositions and dosages.
  • the method can include providing a biological sample from a subject; detecting a presence of an anti-CBl or an anti-CB2 antibody in the biological sample; and determining a presence or likely presence of fibromyalgia if the presence of anti- CB 1 or anti-CB2 antibody is detected.
  • the method can include providing a biological sample from a subject, detecting a level of anti-CBl or anti-CB2 antibodies in the biological sample, and determining a presence or likely presence of fibromyalgia if the level of an anti-CBl or anti-CB2 antibody is higher than an established control level.
  • the established control level is a level of anti-CBl or anti-CB2 antibodies within two standard deviations of anti-CBl or anti-CB2 antibody levels from subjects without fibromyalgia.
  • the method includes providing a biological sample from a subject; detecting a level of anti-CBl or anti-CB2 antibodies in the biological sample; and determining a presence or likely presence of fibromyalgia if the level of anti-CB 1 or anti-CB2 antibodies is significantly higher than an established control level.
  • the established control level is a level of anti-CBl or anti-CB2 antibodies from subjects without fibromyalgia.
  • a “significantly higher” anti-CBl or anti-CB2 antibody level can mean that the antibody level in a subject is higher than the antibody level measured in an normal biological sample (i.e., a biological sample of a healthy subject) by 10% or more, 30% or more, 70% or more, or 100% or more.
  • the term “level” of a component refers to the quantity or concentration of a component present in a sample.
  • Component levels can be measured using any of a variety of well known techniques. The level is typically determined by measuring protein levels, but alternatively the level can be determined in some cases by measuring mRNA levels, which may be followed by conversion of mRNA levels into predicted protein levels.
  • the system can include an isolated biological sample from a subject and an assay for detecting in the biological sample, a presence or level of an anti-CBl or anti- CB 2 antibody.
  • the assay can be any assay that can detect an antibody and/or measure levels of an antibody, such as an immunoassay.
  • the assay can be, but not be limited to, an enzyme-linked immunosorbent assay (ELISA), radio-immunoassay, automated immunoassay, cytometric bead assay, immunoprecipitation assay, and/or the like.
  • ELISA enzyme-linked immunosorbent assay
  • the ELISA can be, but not be limited to quantitative, indirect ELISA, sandwich ELISA, competitive ELISA, multiple and portable ELISA, and/or the like.
  • the assay includes a first reagent to react with the biological sample, a second reagent (e.g., secondary antibody) to react with the anti- CBl or anti-CB2 antibody, and a substrate.
  • the first reagent is CB1 or CB2 or a fragment thereof, which will react with the anti-CBl or anti-CB 2 antibody if present in the biological sample.
  • the second reagent includes a label to produce a signal to indicate the presence of the anti-CBl or anti-CB2 antibody.
  • the label is a radiolabel, a chromophore, a fluorophore, a quantum dot, an enzyme, horseradish peroxidase (HRP), an alkaline phosphatase (AP), biotin, or a combination thereof.
  • the label is an enzyme that will react with the substrate.
  • the first reagent is on a solid phase (e.g., plate, multi-well plate).
  • the assay includes a first reagent to react with the anti- CB1 or anti-CB2 antibody.
  • the first reagent includes a label to produce a signal to indicate the presence of the anti-CBl or anti-CB2 antibody.
  • the label is a radiolabel, a chromophore, a fluorophore, a quantum dot, an enzyme, HRP, an AP, biotin, or a combination thereof.
  • the reagent is on a solid phase (e.g., plate, multi-well plate).
  • the system further includes a machine for determining a presence or likely presence of fibromyalgia if the presence of an anti-CBl or anti-CB2 antibody is detected.
  • the machine is a computer.
  • the computer includes a display element for displaying whether there is a presence or absence of fibromyalgia.
  • the system further includes a machine for determining a presence or likely presence of fibromyalgia if the level of anti-CBl or anti-CB2 antibodies is higher than an established control level.
  • the established control level is a level of anti-CBl or anti-CB2 antibodies within two standard deviations of anti-CBl or anti-CB2 antibody levels from subjects without fibromyalgia.
  • the method further includes analyzing the biological sample for a level of anti-CBl or anti-CB2 antibodies.
  • the anti-CBl or anti-CB2 antibody detected in these methods or systems is an antibody that binds specifically to CB 1 or CB2.
  • the anti-CBl or anti-CB2 antibody is an antibody that binds specifically to a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 residue peptide that has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous residues of CB 1 or CB2.
  • the anti-CB 1 or anti-CB2 antibody binds specifically to a polypeptide comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 residues that has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% homology with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous residues of CB 1 or CB2.
  • the anti-CB 1 or anti-CB2 antibody binds specifically to a polypeptide comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous residues of CB1 or CB2.
  • detecting the presence or absence of the antibody is performed on a biological sample obtained from the subject.
  • the biological sample can be blood, serum, stool, lymph fluid, cerebral, fluid, tissue fluid (such as bone marrow or thymus fluid) and respiratory fluid including nasal and pulmonary fluid and bronchoalveolar lavage, or the like, obtained from the subject.
  • tissue fluid such as bone marrow or thymus fluid
  • respiratory fluid including nasal and pulmonary fluid and bronchoalveolar lavage, or the like.
  • methods and systems that can be used to detect the presence or absence of an antibody that binds specifically to CB 1 or CB2, or a fragment thereof. These methods and systems include but are not limited to ELISA, immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), radioimmunoassays, and affinity purification.
  • CB1 or a fragment thereof or CB2 or a fragment thereof is used as a substrate to bind anti-CR antibodies.
  • detecting the presence or absence of an antibody that binds specifically to CB1 or a fragment thereof or CB2 or a fragment thereof can be performed by contacting CB 1 or a fragment thereof or CB2 or a fragment thereof to a biological sample obtained from the subject to isolate the antibody that binds specifically to CB1 or a fragment thereof or CB2 or a fragment thereof, wherein the isolation of the antibody that binds specifically to CB 1 or a fragment thereof or CB2 or a fragment thereof indicates the presence of the antibody and the lack of isolation of the antibody that binds specifically to CB1 or a fragment thereof or CB2 or a fragment thereof indicates the lack of the antibody.
  • the fragment CB1 or CB2 can be the fragments as described herein.
  • an affinity matrix comprising CB 1 or a fragment thereof or CB2 or a fragment thereof can be bound to a solid support; the biological sample can be contacted to the affinity matrix to produce an affinity matrix- antibody complex (if the antibody is present); the affinity matrix- antibody complex can be separated from the remainder of the biological sample; and the antibody can be released from the affinity matrix.
  • a label e.g., fluorescent label
  • the labeled CB1 or a fragment thereof or CB2 or a fragment thereof can be contacted with a biological sample to allow the antibody (if present) to bind specifically to the labeled CB1 or a fragment thereof or CB2 or a fragment thereof.
  • the labeled CB1 or a fragment thereof or CB2 or a fragment thereof can be separated out and analyzed for its binding to the antibody.
  • Some embodiments of the invention relate to an assay used in any of the foregoing methods.
  • kits using any of the foregoing methods.
  • the method can include an assay used to determine compositions of a substance that has higher binding affinities to CB1 and CB2 compared to an anti-CBl or anti-CB2 autoimmune antibody.
  • the method can include an assay to determine synergistic combinations of substances by comparing binding affinities of various combinations of the substances.
  • the method is used to determine effectivity of various dosages.
  • the assay can be any binding assay known in the art used to determine binding affinities.
  • enzyme-linked immunoassays ELISA
  • RIAs radioimmunoassays
  • the ELISA can include, but not be limited to indirect ELISA, sandwich ELISA, competitive ELISA, multiple and portable ELISA as described above.
  • the method can include determining effectivity of an anti- CB1 or anti-CB2 antibody neutralizing or inhibiting agent for administering the anti- CBl or CB2 antibody neutralizing or inhibiting agent to a subject in need thereof to neutralize or inhibit the anti-CBl or anti-CB2 antibody.
  • the anti- CBl or anti-CB2 antibody neutralizing or inhibiting agent is a compound capable of binding and activating CB 1 or CB2 with a higher affinity than an anti-CB 1 or anti-CB2 antibody.
  • the compound is a cannabinoid in concentrations sufficient to competitively bind the CB1 and/or CB2 and/or otherwise change the conformation at CB1 and/or CB2 sufficient to interfere with binding of autoantibody.
  • the anti-CBl or anti-CB2 antibody neutralizing or inhibiting agent is a compound capable of binding to the anti-CBl or CB2 antibody and neutralizing or inhibiting its function.
  • the method can include determining efficacy of an agent to change CB1 or CB2 from an inactive state to an active state for administering the agent to a subject in need thereof to treat fibromyalgia.
  • the agent to change CB 1 or CB2 from an inactive state to an active state is a compound capable of activating CB1 or CB2.
  • the compound can be a cannabinoid.
  • the method can include determining effectivity of a CB1 or CB2 agonist for administering the CB 1 or CB2 agonist to a subject in need thereof to treat fibromyalgia.
  • the CB 1 or CB2 agonist can be a cannabinoid.
  • the cannabinoid in any method described herein can be
  • the cannabinoid can be, for example, one or more of cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), cannabidiorcol (CBD-C1), delta-9-tetrahydroc
  • the present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of the agents described herein.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
  • the pharmaceutical compositions according to the invention can be formulated for delivery via any route of administration.
  • Route of administration can refer to any administration pathway known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal or parenteral.
  • Transdermal administration can be accomplished using a topical cream or ointment or by means of a transdermal patch.
  • the pharmaceutical compositions based on compounds according to the invention can be formulated for treating the skin and mucous membranes and are in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions.
  • Topical-route compositions can be either in anhydrous form or in aqueous form depending on the clinical indication.
  • Parental refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal.
  • the compositions can be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders.
  • the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release.
  • the compositions can be in the form of solutions or suspensions for infusion or for injection.
  • the compositions can also be administered by vaporization or the like.
  • compositions according to the invention can also contain any pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body.
  • the carrier can be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof.
  • Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it can come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.
  • compositions according to the invention can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers can be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier can also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy and can include milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation can be administered directly p.o. or filled into a soft gelatin capsule.
  • the pharmaceutical compositions according to the invention can be delivered in a therapeutically effective amount.
  • the precise therapeutically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration.
  • Some embodiments provide for a method of treating a subject for fibromyalgia including detecting the presence of anti-CB 1 or anti-CB2 antibodies and administering a composition to the subject.
  • the composition is a composition as described herein and/or a composition determined by any of the methods disclosed herein.
  • the method can include administration of prebiotics and/or probiotics in addition to the composition.
  • Embodiments of the invention relate to various treatment protocols.
  • Treatment protocols can involve use of cannabis-based medicines via oral, oromucosal, and/or topical routes.
  • Treatment protocols can include synthesis of a biological pharmaceutical to serve as an anti-auto-antibody to inactivate endogenous substances in the fibromyalgia patient. This can be administered via periodic intravenous infusion, and/or via the oral route.
  • Treatment protocols can include optimized lifestyle adjustments including, but not limited to, low-impact aerobic exercise and dietary manipulation to include prebiotics and/or probiotics.
  • An example of a putative cannabis-based treatment can relate to use of THC due to its analgesic and sleep-promoting properties, as well as positive effects on the gut microbiome to reduce autoimmune responses.
  • cannabidiol CBD
  • CBD cannabidiol
  • the methods can be used in connection with other autoimmune disorders as defined herein, including, but not limited to, arthritis (acute and chronic, rheumatoid arthritis including juvenile-onset rheumatoid arthritis and stages such as rheumatoid synovitis, gout or gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, degenerative arthritis, type II collagen-induced arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still's disease, vertebral arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, menopausal arthritis, estrogen-depletion arthritis, and ankylosing spondylitis/rheumatoid spondylitis), autoimmune lymphoproliferative disease, inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gut
  • NSIP Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatosis, transient acantholytic dermatosis, cirrhosis such as primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac or Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia such as mixed cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as refractory or relapsed or relapsing polychond
  • the methods can be used in connection with disorders known to be co-morbid with fibromyalgia that affect a subject, including, but not limited to, disorders linked to clinical endocannabinoid deficiency, for example, migraine, irritable bowel syndrome, post-traumatic stress disorder (PTSD), autism, intractable depression, and/or the like (Russo 2004; Russo 2016).
  • disorders linked to clinical endocannabinoid deficiency for example, migraine, irritable bowel syndrome, post-traumatic stress disorder (PTSD), autism, intractable depression, and/or the like (Russo 2004; Russo 2016).
  • a study is done to identify possible autoantibodies to CB1 or CB2 in fibromyalgia as compared to control patients.
  • the study includes 100 patients fulfilling the American College of Rheumatology (ACR) Revised 2010 criteria for diagnosis of fibromyalgia and 100 control patients without fibromyalgia.
  • Serum is collected from all patients and examined for presence or absence of antibodies to human CB1 and CB2 receptors.
  • Exclusion Criteria El. Patient / Subject less than 18 years old; E2. Pregnant or breast-feeding women (to eliminate possibility of changes in immunity attributable to those conditions); E3. Patients with known autoimmune disorders; E4. Patients on steroids or other immunosuppressive drugs; E5.
  • Example 2 Experiments are done to compare levels of anti-CBl or anti-CB2 antibodies in the serum of patients with fibromyalgia compared to healthy subjects.
  • the primary screen is ELISA for antibodies against CB1 or CB2 receptor extracellular domains. Plates are coated with GST fusion proteins corresponding to the extracellular domains of each cannabinoid receptor and testing the serum for antibody /antigen interaction over a range of dilutions. Positives are verified by screening serum by Western blot against human CB1 and CB2 receptor lysates. Immunostaining of human CB1 or CB2- expressing HEK cells are performed to confirm results. A statistically significant difference was found in auto-antibody expression against CB1 and/or CB2 in fibromyalgia patients as compared to controls.
  • This example relates to diagnosing Crohn disease.
  • the presence of an anti-CB 1 or an anti-CB2 antibody is tested in a biological sample from a patient. If the presence of anti-CBl or anti-CB2 antibody is detected, the presence or likely presence of Crohn disease in the subject is determined.
  • This example relates to diagnosing ulcerative colitis.
  • the presence of an anti- CBl or an anti-CB2 antibody is tested in a biological sample from a patient. If the presence of anti-CB 1 or anti-CB2 antibody is detected, the presence or likely presence of ulcerative colitis in the subject is determined.
  • This example relates to an antibody binding inhibition assay to determine effective agents for treatment of an autoimmune disorder.
  • the assay uses various cannabinoids and/or other small molecules to identify effective agents to inhibit the autoimmune antibody binding.
  • a panel of all available cannabinoids in semi-purified or purified form is used in a competitive binding assay in which immobilized CB1 and CB2 receptors are first contacted with the panel of cannabinoids at varying concentrations.
  • Optional washes are conducted in some of the samples to indicate binding stringencies of the various cannabinoids.
  • the contacting step and optional washing step is followed by addition of autoimmune antibody collected from patients or raised in model-system animals.
  • Antibody binding to CB1 and CB2 is measured by binding of a secondary antibody permitting quantitative detection of the complex of the receptor, primary antibody, and secondary antibody.
  • the library of small molecules includes a large number of essential oils, many of which are known to have affinity for G-protein coupled receptors (GPCRs); CB1 and CB2 are both members of the large family of GPCRs, and so the essential oils constitute a diverse and inexpensive, readily available source of small molecules for such an analysis.
  • GPCRs G-protein coupled receptors
  • This example relates to treating a patient with an autoimmune disorder. Volunteer patients are administered a composition with the effective agents identified in Example 6, in various doses. Safety issues are addressed by administering the effective agents within dosage ranges already known to be tolerated by humans in other uses of the effective agents. Particularly in the case of cannabinoids and essential oils, there are abundant data on human uses and tolerated ranges of dosage. Efficacy of the effective agents is assessed, ranked, and optionally correlated with other patient criteria such as age, gender, genotype, and the like. Amelioration of symptoms of the autoimmune disorder is observed in some of the patients, and further trials are designed based upon these data.
  • a patient with an autoimmune disorder is treated with a cannabis-based treatment using THC due to its analgesic and sleep-promoting properties, as well as its positive effects on the gut microbiome to reduce autoimmune responses (further details can be found in Russo EB. Cannabis Therapeutics and the Future of Neurology. Frontiers in Integrative Neuroscience 2018;12:1-11. DOI: 10.3389/fnint.2018.00051; the entire contents of the foregoing are fully incorporated by reference herein). Beneficial effects are observed.
  • the study is expanded to a larger number of patients for quantitative determination of dose/response, taking into account the approach to safety of dosage ranges as discussed in Example 7. Other patient characteristics as discussed in Example 7 are also noted for larger personalized-medicine studies.
  • a patient with an autoimmune disorder is treated with a cannabis-based treatment using CBD which affects auto-antibody binding to the CB1 receptor via its ability to act as a negative allosteric modulator (further details can be found in Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 2015;172(20):4790-805. DOI: 10.1111/bph.13250; the entire contents of the foregoing are fully incorporated by reference herein). Amelioration of symptoms is noted and further studies are conducted as described in Example 8.
  • a patient with an autoimmune disorder is treated with an optimized cannabis- based preparation combining components such as low-dose THC, higher dose CBD, plus select cannabis terpenoids including caryophyllene for analgesia and reduced inflammation without sedation, and linalool for anti-anxiety benefits (additional information can be found in Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163(7): 1344-64. (In eng). DOI: 10.1111/j.1476-5381.2011.01238.x; Russo EB, Marcu J. Cannabis pharmacology: The usual suspects and a few promising leads.
  • any numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the disclosure are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and any included claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are usually reported as precisely as practicable.

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Abstract

L'invention concerne le diagnostic et le traitement de troubles auto-immuns tels que la fibromyalgie. Certains modes de réalisation de l'invention concernent des procédés, des systèmes, des dosages et des kits pour diagnostiquer le trouble auto-immun tel que la fibromyalgie. L'invention concerne également des procédés, des systèmes et des dosages pour déterminer des traitements pour la fibromyalgie, par exemple, un dosage pour déterminer des compositions et des dosages efficaces.
PCT/US2021/026340 2020-04-09 2021-04-08 Diagnostic et traitement de la fibromyalgie Ceased WO2021207466A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040265874A1 (en) * 2000-10-17 2004-12-30 Bio-Rad Laboratories, Inc. Pattern recognition method for diagnosis of systemic autoimmune diseases
US20100273831A1 (en) * 2007-12-17 2010-10-28 Henricus Jacobus Maria Gijsen Fluoro alkyl substituted benzimidazole cannabinoid agonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040265874A1 (en) * 2000-10-17 2004-12-30 Bio-Rad Laboratories, Inc. Pattern recognition method for diagnosis of systemic autoimmune diseases
US20100273831A1 (en) * 2007-12-17 2010-10-28 Henricus Jacobus Maria Gijsen Fluoro alkyl substituted benzimidazole cannabinoid agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOEBEL ANDREAS, CLIVE GENTRY , ULKU CUHADAR , EMERSON KROCK, NISHA VASTANI, SERENA SENSI, KATALIN SANDOR, ALEXANDRA JURCZAK, AZAR : "Passive transfer of fibromyalgia pain from patients to mice", BIORXIV PREPRINT, 24 July 2019 (2019-07-24), XP055865153, Retrieved from the Internet <URL:http://dx.doi.org/https://doi.org/10.1101/713495> [retrieved on 20211124], DOI: https://doi.org/10.1101/713495 *

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