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WO2025091116A1 - Traitement et prophylaxie de la migraine - Google Patents

Traitement et prophylaxie de la migraine Download PDF

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Publication number
WO2025091116A1
WO2025091116A1 PCT/CA2024/051429 CA2024051429W WO2025091116A1 WO 2025091116 A1 WO2025091116 A1 WO 2025091116A1 CA 2024051429 W CA2024051429 W CA 2024051429W WO 2025091116 A1 WO2025091116 A1 WO 2025091116A1
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formulation
migraine
treatment
cbc
cannabinoid
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Mahsa ABRISHAMI
Landon K PASTUSHOK
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Zyus Life Sciences Inc
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Zyus Life Sciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol

Definitions

  • the present disclosure relates generally to a formulation for prophylactic or medicinal use. More particularly, the present disclosure relates to cannabinoid formulations for use in prevention or treatment of migraine and/or management of migraine pain, and biomarkers for use in monitoring individuals.
  • Migraine is a complex and heterogeneous neurological disorder that leads to significant debilitation in millions of people worldwide.
  • Food and Drug Administration updated the guidance for the acute migraine treatment trials to evaluate treatment efficacy based on pain freedom and freedom from the most bothersome symptoms, including photophobia, phonophobia or nausea at 2 hours as determined by patients (Ocheretyaner et al., 2022).
  • Current FDA-approved drugs for migraine in adults exert their activity by blocking CGRP, the key neurotransmitter in the pathogenesis of migraines. Targeting CGRP is suggested to reduce the frequency and severity of migraine episodes.
  • most of the approved drugs for migraine in adults are intended for migraine prevention with limited optionality for migraine treatment.
  • Cannabinoids are a group of structurally similar compounds isolated from cannabis plants, which activate cannabinoid receptors in cells.
  • Cannabinoids may be synthesized or may be isolated from cannabis plants or plant extracts (herein: a cannabinoid-containing plant extract).
  • Cannabinoids can be isolated from plants or extracts to the extent that they are obtained in nearly pure, or essentially pure form, free of significant amounts of other naturally occurring compounds, such as other cannabinoids or plant-derived molecules such as terpenes.
  • cannabinoids include but are not limited to tetrahydrocannabinol (THC); cannabidiol (CBD), cannabichromene (CBC); tetrahydrocannabidivarin (THCV); tetrahydrocannabinolic acid (THCA); cannabigerol (CBG); cannabidivarin (CBDV), cannabinol (CBN), and cannabidiolic acid (CBDA).
  • Cannabis plants may be bred to have different amounts of a certain cannabinoid, as may be desirable for different purposes.
  • THC and CBD have, to date, been considered as the predominant cannabinoids of interest.
  • a 9 -THC exerts partial agonistic activity on CB1 and CB2 receptors with high binding affinity with CB1 receptor leading to its psychoactive activity.
  • Cannabichromene is a major non-psychotropic cannabinoid naturally found in the Cannabis sativa plant (ElSohly M 2014).
  • CBC has moderate affinity (Ki ⁇ 100 nanomolar) only for CB2 receptors and binds to CB1 receptors only at concentrations higher than 1 micromolar (Shinjyo N 2013).
  • the major CBC activity in brain has been suggested to be partly dependent on indirect activation of CB1 receptor by inhibition of cellular uptake of anandamide (De Petrocellis L 2011) and activation of TRPA1 (Transient Receptor potential A1) channels (Izzo and Capasso R 2012).
  • TRPA1 Transient Receptor potential A1
  • CBC is found to be the most potent agonist of all the phytocannabinoids at TRPA1 channels (Maione S 2011).
  • CBC has also shown antiinflammatory effects (Izzo and Capasso R 2012).
  • CBD can act synergistically with A 9 -THC and contribute to the analgesic effect of medicinal-based cannabis extract (Russo 2011).
  • the agonistic activity of CBC with CB1 and CB2 receptors can offer a promising approach to potentiate the effect of other cannabinoids that exert their activities via binding and activation of CB1 an CB2 receptors.
  • Medicinal uses of cannabinoids are known, and formulations specifically to treat pain have been described.
  • W02007/083098 A1 (GW Pharma Ltd) describes cannabinoid-containing plant extracts for treatment of neural degeneration.
  • U.S. Patent Publication No. US2016/0106705 (United Cannabis Corp.) describes cannabis extracts having at least four cannabinoids and a terpene or flavonoid for use in relieving anxiety, pain, and related disorders.
  • WO2016/044370 A1 India Globalization Capital Inc. teaches a topical pain-relieving formulation containing a combination of THC, CBD and cobalamin.
  • WO2013/165251 A1 ECHO Pharmaceuticals BV describes a thin film evaporation method for obtaining THC-containing isolates, which may have trace only amounts of CBN or CBD.
  • WO2012/144892 A1 the use of acidic cannabinoids such as THC, CBD, and other cannabinoids for enhancing an animal’s natural cellular resistance to disease is described.
  • WO2012/160358 A1 the use of at least one of CBG, CBC, CBDV and THCV as a treatment of neuropathic pain is described.
  • WO2021/212209 A1 (Zyus Life Sciences Inc.) describes the use of a cannabichromene formulation for pain management is described.
  • W02020/223800 A1 (Zyus Life Sciences Inc.) describes the use of a cannabinoid formulation containing cannabichromene is described for use in pain management.
  • CBC Cannabichromene
  • the formulation described herein is for use in treatment or prevention of migraine.
  • a formulation for use in a method of treatment or prophylaxis of migraine in a subject in need thereof comprising a primary cannabinoid and one or more excipient, diluent or carrier, wherein said primary cannabinoid is cannabichromene (CBC).
  • CBC cannabichromene
  • the formulation may be essentially free of tetrahydrocannabinol (THC).
  • the formulation may comprise one or more secondary cannabinoids, preferably cannabidiol (CBD). When present, the one or more secondary cannabinoids may be present in an amount of up to 15% by weight of the primary cannabinoid.
  • the formulation may be prepared in a dosage form selected from the group consisting of a pill, tablet, gel capsule, syrup, oil-based spray, topical or nasal formulation, and liquid oil form.
  • the formulation may provide a total amount of from about 10 mg to about 200 mg of primary cannabinoid per dose, preferably from about 10 mg to about 100 mg per dose, or from about 20 mg to about 50 mg per dose.
  • a method for treatment or prophylaxis of migraine in a subject in need thereof, comprising administering to said subject an effective amount of a formulation comprising a primary cannabinoid and an excipient, diluent or carrier, wherein said primary cannabinoid is cannabichromene (CBC).
  • CBC cannabichromene
  • the formulation used may be essentially free of tetrahydrocannabinol (THC). Further, the formulation may additionally comprise one or more secondary cannabinoids, preferably cannabidiol (CBD). When present, the one or more secondary cannabinoids may be present in the formulation in an amount of up to 15% by weight of the primary cannabinoid.
  • the formulation administered in this method may be in a dosage form selected from the group consisting of a pill, tablet, gel capsule, syrup, oil-based spray, topical or nasal formulation, and liquid oil form.
  • the formulation may provide the subject with a total amount of from about 10 mg to about 200 mg of primary cannabinoid per dose, preferably from about 10 mg to about 100 mg per dose, or from about 20 mg to about 50 mg per dose.
  • This method for treatment or prophylaxis of migraine may further comprise the step of evaluating CALC or TRPM8 gene expression following administration to determine migraine status.
  • a formulation for treating migraine in a subject in need thereof, in which the formulation comprises an effective amount of a primary cannabinoid and an excipient, diluent or carrier, and the primary cannabinoid consists of cannabichromene (CBC).
  • CBC cannabichromene
  • a use of a formulation for preparation of a medicament for treating migraine in a subject in need thereof is also described, in which the formulation comprises an effective amount of a primary cannabinoid and an excipient diluent or carrier, and in which the primary cannabinoid consists of cannabichromene (CBC).
  • the formulation may be essentially free of tetrahydrocannabinol (THC).
  • the formulation may additionally comprising one or more secondary cannabinoids, such as preferably cannabidiol (CBD).
  • CBD cannabidiol
  • the one or more secondary cannabinoids may be used in an amount of up to 15% by weight of the primary cannabinoid.
  • the formulation may be prepared in a dosage form selected from the group consisting of a pill, tablet, gel capsule, syrup, oil-based spray, topical or nasal formulation, and liquid oil form.
  • the formulation may provide a total amount of from about 10 mg to about 200 mg of primary cannabinoid per dose, preferably from about 10 mg to about 100 mg per dose, or from about 20 mg to about 50 mg per dose.
  • a method for identifying a subject responsive to CBC for treatment or prophylaxis of migraine, the method comprising evaluation of CALC and TRPM8 gene expression, upon treatment with CBC, and determining a responsive subject as having downregulated expression following CBC treatment.
  • Figure 3 depicts differential expression of the TRPM8 gene in the spinal cord of SNL rats pre-surgery vs. post-surgery.
  • Figure 4 depicts differential expression of the CALCA gene in the spinal cord collected from SNL rats following treatment with Cannabichromene (CBC; 10 mg/Kg; p.o.), morphine (10 mg/Kg; i.p.), or vehicle daily for 20 days.
  • Figure 5 depicts differential expression of the CALCB gene in the spinal cord collected from SNL rats following treatment with Cannabichromene (CBC; 10 mg/Kg; p.o.), morphine (10 mg/Kg; i.p.), or vehicle daily for 20 days.
  • the present disclosure provides a cannabichromene formulation for treating migraine, and for preventing, monitoring and managing pain associated with migraine. It has not previously been recognized that cannabichromene can have an effect on migraine treatment and biomarkers thereof when relied upon as the primary cannabinoid in a formulation.
  • a formulation for treating and preventing migraine comprising cannabichromene as the primary cannabinoid together with an excipient. Methods of use of the formulation, doses and dosage forms are described. Correlations between CALC and TRPM8 gene expressions in migraine pain were found, with downregulated expression resulting from CBC treatment. The use of these biomarkers is described for use in monitoring treatment, prevention or onset of migraine in subjects using CBC. [0037] The described methods and uses for treatment or prevention of migraine involve modulating the expression of alpha-calcitonin and beta-calcitonin gene-related peptides (a-CGRP and p-CGRP, respectively), neuropeptides that are involved in migraine pathophysiology.
  • a-CGRP and p-CGRP beta-calcitonin gene-related peptides
  • Migraine is a common type of headache disorder that stands as the second highest cause of disability with estimated prevalence of about 15% globally.
  • the cannabinoid formulation described herein comprises primarily cannabichromene together with an excipient.
  • TRPM8 Transient Receptor Potential Cation Channel Subfamily M Member 8
  • RNA sequencing permits monitoring of migraine treatment. This permits an effective non-psychoactive therapy for migraine pain, migraine attacks and migraine prevention, based on the gene expression profile of patients, where patient response to cannabichromene treatment can be predicted by such biomarkers and can benefit personalized therapy.
  • a formulation for use in migraine treatment of a subject in need thereof comprises a primary cannabinoid and an excipient.
  • the primary cannabinoid consists of cannabichromene (CBC).
  • CBC cannabichromene
  • the formulation is essentially free of tetrahydrocannabinol (THC), meaning that small and insignificant amount may be present, for example at an amount of 1% or less by weight of the CBC.
  • THC tetrahydrocannabinol
  • a formulation for use in a method of treating migraine by a subject in need thereof, said formulation comprising a primary cannabinoid and an excipient, carrier, or diluent wherein said primary cannabinoid consists of cannabichromene (CBC), and wherein said formulation is essentially free of tetrahydrocannabinol (THC).
  • Essentially free may mean an insignificant amount, for example at 1% by weight or less, 0.5% by weight or less, or 0.1% by weight or less as compared with the weight of the primary cannabinoid.
  • the formulation may additionally comprise one or more secondary cannabinoids, preferably cannabidiol (CBD).
  • CBD cannabidiol
  • the formulation may comprise the one or more secondary cannabinoids in an amount of up to 15% by weight of the primary cannabinoid.
  • the formulation may be prepared in a dosage form selected from the group consisting of a pill, tablet, gel capsule, syrup, oil-based spray, topical or nasal formulation, and liquid oil form.
  • the formulation may provide a total amount of from about 10 mg to about 200 mg of primary cannabinoid per dose, preferably from about 10 mg to about 100 mg, or about 20 mg to about 50 mg. On a daily basis, amounts used can vary widely depending on the individual’s tolerance, body weight, and the extent of the pain endured from migraine.
  • a method for migraine treatment for use by a subject in need thereof, comprising administering to said subject an effective amount of a formulation comprising a primary cannabinoid and an excipient, wherein said primary cannabinoid consists of cannabichromene (CBC), and wherein said formulation is essentially free of tetrahydrocannabinol (THC).
  • a formulation comprising a primary cannabinoid and an excipient, wherein said primary cannabinoid consists of cannabichromene (CBC), and wherein said formulation is essentially free of tetrahydrocannabinol (THC).
  • CBC cannabichromene
  • the formulation may additionally comprise one or more secondary cannabinoids, preferably cannabidiol (CBD).
  • CBD cannabidiol
  • the formulation used in the method may involve the one or more secondary cannabinoids being present in the formulation in an amount of up to 15% by weight of the primary cannabinoid.
  • the method may involve administration in a dosage form selected from the group consisting of a pill, tablet, gel capsule, syrup, oil-based spray, topical or nasal formulation, and liquid oil form.
  • the method may comprise administration to the subject an amount of the formulation that provides to the subject a total amount of from about 10 mg to about 200 mg of primary cannabinoid per dose, preferably from about 10 mg to about 100 mg or from about 20 mg to about 50 mg per dose.
  • Primary Cannabinoid The term “primary” is meant to indicate the cannabinoid that is primarily responsible for the intended effect of migraine treatment, as described herein. CBC is the primary cannabinoid, and it has been found to be effective when used without significant amounts of other cannabinoids in the context of migraine treatment and/or pain management attributable to migraine. If another cannabinoid is present in the formulation in a lower amount, the quantity present would not render it a “primary” cannabinoid. But other cannabinoids can be present in the formulation as secondary cannabinoids.
  • the primary cannabinoid, CBC may be present in the formulation from natural sources, such as from one or more cannabis plants, an in particular extracts thereof. Or the primary cannabinoid may be obtained from one or more isolated sources, or from a synthetic source where one or more of the desired cannabinoids is synthesized.
  • a blend of natural and synthetic cannabinoids may be used so that a natural source with a variable content (due to growing conditions or other reasons), may be standardized to pre-determined amounts using adjustment with synthetic or isolated sources.
  • An extract may be obtained from a plant that is specially modified or grown under conditions conducive to production of a cannabinoid ratio particularly suited to the desired primary cannabinoid ratio, without needing to dramatically alter or supplement the amount of any of the primary cannabinoids present.
  • cannabinoids is desired extraction methods such as an ethanolic extraction, or a CO 2 based extraction may be used.
  • Cannabinoids may be incidentally present in the formulation, and if present, the quantities of such additional cannabinoid ingredients would not reduce or significantly influence the migraine treatment feature of the formulation.
  • the formulation may be used by humans or by pets (companion animals such as dogs or cats), as well as for working animals such as horses, where migraine has been detected.
  • Subjects in need of a therapeutic effect for migraine treatment may use the formulation prior to, during, or after the migraine event or as need arises.
  • Migraine pain can be debilitating for a number of reasons. Management with the formulation described herein can avoid problems or side effects inherent with other migraine medications.
  • the formulation may be used prophylactically to lessen the pain that is anticipated when an individual feels a migraine coming on.
  • Biomarkers of migraine shown herein to be responsive to CBC treatment may be monitored in samples from individuals susceptible to migraine to compare with a self-reference to as to determine efficacy of treatment and monitor for migraine onset or improvement while a subject is undergoing treatment or prophylactic use.
  • the formulation is amenable to oral delivery, such as in a pill, tablet, gel capsules, syrup, oil-based spray, topical or nasal formulation, or liquid oil form.
  • the oral form may be provided in a food or as a food supplement, which may be added to a food to be more palatable or readily consumed by a subject.
  • Topical or nasal absorption is possible, such as in the form of a cream, gel or spray.
  • a fat-soluble carrier, or nano- or micro-particles or emulsions may be used so that the highly fat-soluble cannabinoids can be more readily absorbed.
  • the formulation may be prepared as an injectable, for intravenous, intramuscular, or intraocular delivery.
  • the formulation may be delivered in a vapor, such as by vaping, in a vaporizer or puffer, or may be heated to cause volatilization and inhalation which could be considered as “smoking”.
  • CBC is the primary cannabinoid in the dosage form of the formula.
  • Other cannabinoids may be present in the formulation.
  • the total amount of primary cannabinoid may range from 10 mg - 200 mg, for example 10 mg - 100 mg, or 20 mg - 50 mg per dose.
  • amounts may be expressed on a mg/mL basis, such as from 1 mg/mL - 200 mg/mL, for example 1 mg/mL - 100 mg/mL, or 5 mg/mL - 50 mg/mL, such that requisite doses may be calculated on a volume basis.
  • Dosages may be used as needed depending on the severity of the migraine experienced, but an individual may wish to use the formulation on an as-needed basis, ranging from once per day (or less, if not needed) to more frequently such as taking 6 doses per day, with a frequency of every 4 hours.
  • An exemplary formulation may be a solid dosage form such as a pill, tablet, or granule-containing capsule.
  • the formulation may be liquid-based, and may contain isolated or synthetic primary cannabinoid, or may be an oil-based extract of cannabis with significant quantities of CBC.
  • the formulation may be in liquid forms such as oil, and oil-based spray, or a liquid-containing gel capsule (soft-gel capsule).
  • a topical or nasal formulation may be prepared, such as a cream, gel or spray. If liquid-containing or gel-containing capsules are used, these may be limited in volume, for example an approximate volume of 200 pL.
  • the milligram quantity stated above as a dosage range may be included in each such capsule, or the capsules may be formulated so as to be less concentrated in units of mg/mL. When less concentrated capsules are used, then the appropriate dosage is delivered by increasing the number of capsules consumed per dose.
  • An individual with migraine may consume orally, on an as-needed or regular basis such as every 6-hours, a dose of the following oil-based cannabinoid formulation.
  • the formulation may comprise 20 mg/mL CBC, and 1 mg/mL CBD, in an oil-based liquid.
  • the individual may take 1 mL orally.
  • initially, the individual may begin by consuming 1 mL of the formulation as-needed or at a frequency of twice per day.
  • the dose may be titrated to a higher amount over time as the individual becomes accustomed to the formulation, until a dose of 1 to 2 mL, taken from 4 to 6 times per day is reached.
  • the formulation may incorporate any acceptable carriers, excipients, diluents, or other ingredients (such as colouring, for example), as may be known in formulating drugs or cannabinoid formulations.
  • Such ingredients may include starch, cellulose, alginates, colloidal silicon, lubricants such as stearates, salts, aqueous and non-aqueous (fat soluble) ingredients.
  • lubricants such as stearates, salts, aqueous and non-aqueous (fat soluble) ingredients.
  • Biomarker Monitoring Evaluation of biomarkers indicative of migraine status, such as CALCA, CALCB, or TRPM8 gene expression in a body fluid, the downregulation of which is indicative of improvement in migraine status. Persons readily responding to CBC treatments can be identified, and also the need for or efficacy of treatment or prevention strategies involving CBC can be evaluated.
  • Migraine Types may be classified according to accompanying symptoms. Migraines may be classified as migraine with or without aura (the two most common classifications) or as migraine with typical aura, migraine with brainstem aura, hemiplegic migraine, retinal migraine, or chronic migraine, with the term “aura” indicating neurological symptoms accompanying the migraine, such as vision blurring, or tingling or numbness in limbs.
  • Migraine is a complex and heterogeneous neurological disorder that leads to significant debilitation in millions of people worldwide.
  • CALCA and CALCB are the encoding genes for alpha-calcitonin and betacalcitonin gene-related peptide (a-CGRP and p-CGRP, respectively), neuropeptides that are involved in migraine pathophysiology.
  • CALCA and CALCB are associated with each other in migraine because they both influence the levels of CGRP and its receptors in the trigeminovascular system, which mediates the pain and inflammation associated with migraine attacks.
  • Human CALCA and CALCB differ only by three amino acids, and, in consequence, similar biological activities are shared.
  • CALCA is considered the principal form of CGRP found in the central and peripheral nervous systems, while CALCB is found mainly in the enteric nervous system (Ocheretyaner ER., et al, 2022).
  • the CALCB region has been identified as a migraine risk locus in a genome-wide association study (GWAS) with over a hundred thousand migraine cases (Hautakangas et al. 2022).
  • p-CGRP is a splice variant of alpha-calcitonin gene-related peptide (a- CGRP), which is encoded by the CALCA gene. Both a-CGRP and p-CGRP can bind to the same receptors and have similar biological effects, such as vasodilation, inflammation, and pain modulation (Messoud A, et al., 2021).
  • CALCA CALCA
  • CALCB CGRP-2
  • CGRP may also play a role in the transition of acute migraine condition to chronic, as chronic migraine patients have higher CGRP levels than episodic migraine patients (Ocheretyaner et al., 2022).
  • CALCA and CALCB may also have distinct roles in migraine subtypes (Ocheretyaner et al., 2022).
  • CALCA and CALCB were shown to be expressed in different subsets of neurons, with distinct molecular signatures and functional properties (Fila et al., 2022).
  • TRP Transient receptor potential
  • TRP channels play a key role in how pain signals are generated and transmitted and can offer potential targets for pain management (Spekker et al., 2023). Studies support that blocking CGRP receptors can reduce the activity of TRP channels. Similarly, TRP channels can also trigger the release of CGRP (Weyer et al., 2017). TRPM8 antagonists have shown therapeutic effects for chronic pain, migraine or inflammation by suppressing cold pressor response to cold- induced allodynia, or to chemotherapy-induced cold allodynia (Spekker et al., 2023).
  • TRPM8 is involved in the regulation of autonomic and behavioral thermos-effectors associated with body temperature maintenance and TRPM8 antagonists have shown body temperature decrease in rodents (Almedia et al., 2012). TRP channels and their involvement in migraine therapy is supported by the clinical success of CGRP receptor antagonism and induction of CGRP release by activation of TRP channels (Dussor et al., 2014)
  • tissue samples from the dorsal root ganglion (DRG) and spinal cord (SC) tissue samples were collected from 50 rats, collected in sterile Hibernate A (BrainBits, www.Transnetyx.com) containing B27 (GIBCOTM) and GLUTAMAXTM supplement (GIBCOTM).
  • the experiments were conducted in strict accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, Canada, 2011) and in accordance with European Union Directive 2010/63 and the Dutch law. The experiments were approved by the Animal Welfare Body (Instantie voor Dierenwelzijn, the Netherlands). Five samples were taken from each tissue type for the following groups:
  • Ribosomal RNA were removed from RNA samples using biotinylated, target-specific oligonucleotides covalently bound to Ribo-Zero rRNA removal beads. Following purification, RNA samples were fragmented into small pieces using divalent cations under elevated temperature. RNA fragments were then retro-transcribed into first strand cDNA using reverse transcriptase and random primers, followed by second strand cDNA synthesis using DNA Polymerase I and RNase H. The cDNA fragments were then subjected to the addition of a single "A" nucleotide and subsequent ligation of adapter. The products were purified and enriched by PCR to create the final cDNA library.
  • rRNA Ribosomal RNA
  • Quality Control and Exploratory Data Analysis Upstream quality control. 100 paired FASTQ files, corresponding to 50 dorsal root ganglion (DRG) samples and 50 spinal cord (SC) samples, were received for quality control (QC) evaluation. A preliminary QC of the raw reads was performed prior to further processing. [0084] Overall, read quality was consistently high; however, all samples showed a high proportion of adapter content, identified by FastQC as "Illumina Universal Adapter". Therefore, the parameters of STAR were adjusted to allow soft clipping of up to 50% of the read. Approximately 60-70% of read-pairs were uniquely mapped to a region of the genome in each sample. [0085] Quality Control and Exploratory Data Analysis: Downstream quality control.
  • Quality control assessment and exploratory data analysis were performed by manually inspecting density, MA and PCA plots, the correlation heatmap and PCA association plots as well as using automated outlier tests, namely distance, Kolomogorov- Smirnov, correlation and Hoeffding's D. Samples were classed as outliers if they failed two or more tests. All samples derived from DRG tissue passed the QC at both the raw and normalised data stages. Two samples derived from SC tissue failed the QC at the raw stage (R02_30 and R02_38). However, after normalisation both samples passed all four outlier tests and were retained for analysis. Therefore, all 100 samples were included in the downstream statistical contrasts.
  • Congruence Analysis was performed to evaluate the level of overlap in gene expression changes between i) DRG tissue and spinal cord tissue, and ii) the different treatments vs vehicle controls, within DRG tissue and SC tissue separately.
  • RNA sequencing is utilized herein, providing a powerful tool for identifying the effect of cannabichromene on differentially expressed genes involved in migraine.
  • DEG dorsal root ganglion
  • Figure 1 depicts differential expression of the CALCA gene in the spinal cord of SNL rats pre-surgery vs. post-surgery.
  • Figure 2 depicts differential expression of the CALCB gene in the spinal cord of SNL rats pre-surgery vs. post-surgery.
  • Figure 3 depicts differential expression of the TRPM8 gene in the spinal cord of SNL rats pre-surgery vs. post-surgery.
  • Figure 4 depicts differential expression of the CALCA gene in the spinal cord collected from SNL rats following treatment with Cannabichromene (CBC; 10 mg/Kg; p.o.), morphine (10 mg/Kg; i.p.), or vehicle daily for 20 days.
  • Figure 5 depicts differential expression of the CALCB gene in the spinal cord collected from SNL rats following treatment with Cannabichromene (CBC; 10 mg/Kg; p.o.), morphine (10 mg/Kg; i.p.), or vehicle daily for 20 days.
  • Figure 6 depicts differential expression of the TRPM8 gene in the spinal cord collected from SNL rats following treatment with vehicle, morphine (10 mg/Kg; i.p.), or Cannabichromene (CBC; 10 mg/Kg; p.o.) daily for 20 days.
  • morphine 10 mg/Kg; i.p.
  • CBC Cannabichromene
  • CGRP calcitonin gene-related peptide

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Abstract

L'invention concerne une méthode de traitement ou de prévention de la migraine qui consiste à moduler l'expression des peptides liés au gène de l'alpha-calcitonine et de la bêta-calcitonine (α-CGRP et β-CGRP, respectivement), des neuropeptides qui interviennent dans la pathophysiologie de la migraine. La migraine est un type commun de céphalée qui représente la seconde cause la plus élevée d'incapacité avec une prévalence estimée d'environ 15 % dans le monde. L'invention concerne une formulation de cannabinoïdes comprenant principalement du cannabichromène conjointement avec un excipient. L'invention concerne une méthode de détection de la corrélation entre des gènes CALCA et CALCB avec TRPM8 (membre 8 de la sous-famille M des canaux cationiques à potentiel de récepteur transitoire) dans la moelle épinière à l'aide d'un séquençage d'ARN. L'invention concerne une thérapie non psychoactive efficace pour la douleur migraineuse, les crises migraineuses et la prévention de la migraine, sur la base du profil d'expression génique de patients, où la réponse du patient au traitement par cannabichromène peut être prédite par de tels biomarqueurs et bénéficier d'une thérapie personnalisée.
PCT/CA2024/051429 2023-11-02 2024-10-30 Traitement et prophylaxie de la migraine Pending WO2025091116A1 (fr)

Applications Claiming Priority (2)

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WO2012160358A1 (fr) * 2011-05-20 2012-11-29 Gw Pharma Limited Cannabinoïdes destiné être utilisé dans le traitement de la douleur neuropathique
WO2016092539A1 (fr) * 2014-12-07 2016-06-16 One World Cannabis Ltd Utilisation de cannabis pour traiter la migraine
US20190275270A1 (en) * 2018-03-07 2019-09-12 Richard Postrel System and method for arresting debilitating migraine events
WO2021212209A1 (fr) * 2020-04-24 2021-10-28 Zyus Life Sciences Inc. Formulation de cannabichromène pour la prise en charge de la douleur
WO2022212351A1 (fr) * 2021-03-29 2022-10-06 Schedule 1 Therapeutics, Inc. Compositions comprenant des cannabinoïdes et méthodes d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012160358A1 (fr) * 2011-05-20 2012-11-29 Gw Pharma Limited Cannabinoïdes destiné être utilisé dans le traitement de la douleur neuropathique
WO2016092539A1 (fr) * 2014-12-07 2016-06-16 One World Cannabis Ltd Utilisation de cannabis pour traiter la migraine
US20190275270A1 (en) * 2018-03-07 2019-09-12 Richard Postrel System and method for arresting debilitating migraine events
WO2021212209A1 (fr) * 2020-04-24 2021-10-28 Zyus Life Sciences Inc. Formulation de cannabichromène pour la prise en charge de la douleur
WO2022212351A1 (fr) * 2021-03-29 2022-10-06 Schedule 1 Therapeutics, Inc. Compositions comprenant des cannabinoïdes et méthodes d'utilisation

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