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WO2025212841A1 - Compositions et méthodes de traitement de maladies et de troubles associés à une faiblesse musculaire - Google Patents

Compositions et méthodes de traitement de maladies et de troubles associés à une faiblesse musculaire

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Publication number
WO2025212841A1
WO2025212841A1 PCT/US2025/022885 US2025022885W WO2025212841A1 WO 2025212841 A1 WO2025212841 A1 WO 2025212841A1 US 2025022885 W US2025022885 W US 2025022885W WO 2025212841 A1 WO2025212841 A1 WO 2025212841A1
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WO
WIPO (PCT)
Prior art keywords
ribitol
serm
administered
dose
combination
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/022885
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English (en)
Inventor
Qi Long Lu
Anthony BLAESER
Bo Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wake Forest University Health Sciences
Original Assignee
Wake Forest University Health Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wake Forest University Health Sciences filed Critical Wake Forest University Health Sciences
Publication of WO2025212841A1 publication Critical patent/WO2025212841A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms

Definitions

  • Dystroglycanopathies are a subset of muscular dystrophies characterized by a secondary defect in glycosylation of alpha-dystroglycan (a-DG). The diseases have been linked to autosomal-recessive mutations in at least 18 different genes.
  • FKRP fukutin like-acetylglucosaminyltransferase (LARGE), POMGnTl, P0MT1, P0MT2, Isoprenoid Synthase Domain Containing (ISPD), Transmembrane protein 5 (TMEM5), l,3-N- acetylglucosaminyltransferase 1 (B3GNT1), glycosyltransferase-like domain containing 2 (GTDC2), p3-N-acetylgalactosaminyltransferase 2 (B3GALNT2), DOLK, GMPPB, DMP2 , DMP3 and SGK196.
  • FKRP fukutin like-acetylglucosaminyltransferase (LARGE), POMGnTl, P0MT1, P0MT2, Isoprenoid Synthase Domain Containing (ISPD), Transmembrane protein 5 (TM
  • Fukutin and Fukutin related protein (FKRP) genes have been recently proposed as Ribitol-5-P transferase that transfers the phosphorated ribitol to the core sugar chain of a-DG.
  • LARGE protein acts as a bifunctional glycosyltransferase, xylosyltransferase and glucuronyltransferase, producing repeating units of [- 3-xylose- a 1,3 -glucuronic acid- 1-] that is the functional glycan chain linking cell membrane protein and extracellular matrix proteins.
  • This LARGE glycan chain is linked to the core O- mannosyl glycans by tandem ribitols. This linkage is critical for muscle health and lack of FKRP function as the result of gene mutations therefore prevents the production of functional glycosylation of a-DG, and disrupts normal interaction between membrane and connective tissues, leading to muscle fiber damage and muscular dystrophy.
  • Mutations in the FKRP gene cause a wide spectrum of disease from a milder form of limbgirdle muscular dystrophy (LGMD2I) to severe Walker-Warburg syndrome (WWS), muscle-eye- brain disease (MEB), and congenital muscular dystrophy type ID (MDC1D).
  • LGMD2I limbgirdle muscular dystrophy
  • WWS muscle-eye- brain disease
  • MDC1D congenital muscular dystrophy type ID
  • AAV Adeno-associated virus
  • ribitol treatment adeno-associated virus
  • AAV gene therapy has demonstrated significant effect to delay and even to stop disease progression in mouse models bearing mutations detected in patients.
  • AAV gene therapy includes most critically the dose-related toxicity and variation (heterogeneity) in transgene expression from muscle to muscle and between muscle fibers within a single muscle.
  • Clinical trials have reported fatality closely related to doses at or higher than IxlO 14 AAV virus particles/kg body weight (BW).
  • Figure 2 is a series of microscopy images showing the effect of 12-month treatments of tamoxifen (Tam), ribitol (rib), and a combination of tamoxifen and ribitol (Tam+rib) in FKRP P448L mutant mice (Untreated) compared to control C57 mice on the histology in the tibialis anterior (TA) or diaphragm muscle.
  • Tam tamoxifen
  • ribitol ribitol
  • Tam+rib a combination of tamoxifen and ribitol
  • Figure 3 is a series of graphs showing the body weight and treadmill exercise tests after 12-month treatments of tamoxifen (Tam), ribitol, and a combination of tamoxifen and ribitol (Tam+ribitol) in FKRP P448L mutant mice (P448L-saline) compared to control C57 mice.
  • FIG 4, panel A is a series of microscopy images with H&E staining showing the effect of 12-month treatments of low-dose tamoxifen, ribitol, a combination of low-dose tamoxifen and ribitol, low-dose raloxifene, and a combination of low-dose raloxifene and ribitol in FKRP P448L mutant mice compared to control C57 (Control) mice on the histology in the tibialis anterior (TA), diaphragm (Diaph), or heart (Heart) muscle.
  • TA tibialis anterior
  • Diaph diaphragm
  • Heart heart
  • panel B is a series of graphs showing the change in centrally nucleated fibers (% CNF) in the in the tibialis anterior (TA) or diaphragm (Diaph) after 12-month treatments of low-dose tamoxifen (Tam), ribitol (Rib), a combination of low-dose tamoxifen and ribitol (Tam/Rib), low-dose raloxifene (Rai), and a combination of low- dose raloxifene and ribitol (Ral/Rib) in FKRP P448L mutant mice compared to control C57 (Cont) mice.
  • * P ⁇ 0.05 compared to untreated control.
  • Figure 7 is a series of graphs showing the body weight and treadmill exercise tests after 6- or 12-month treatments of tamoxifen (Tam), ribitol (Rib), and a combination of tamoxifen and ribitol (Tam/Rib), low-dose raloxifene (Rai), and a combination of low-dose raloxifene and ribitol (Ral/Rib) in FKRP P448L mutant mice compared to control C57 (Cont) mice.
  • * P ⁇ 0.05 compared to untreated control.
  • Figure 8 is a series of graphs showing whole body plethysmography tests after 6- or 12- month treatments of tamoxifen (Tam), ribitol (Rib), and a combination of tamoxifen and ribitol (Tam/Rib), low-dose raloxifene (Rai), and a combination of low-dose raloxifene and ribitol (Ral/Rib) in FKRP P448L mutant mice compared to both untreated FKRP P448L mutant mice , with C57 mice as controls (Cont).
  • Whole body plethysmography parameters include inspiratory time (Ti), expiratory time (Te), peak inspiratory flow (PIF), peak expiratory flow (PEF), end inspiratory pause (EIP), end expiratory pause (EEP), frequency (F), minute volume (MV), and enhanced pause (Penh).
  • I inspiratory time
  • Te expiratory time
  • PPF peak inspiratory flow
  • PEF peak expiratory flow
  • EIP end inspiratory pause
  • EEP end expiratory pause
  • F minute volume
  • Penh enhanced pause
  • Figure 10 is a series of graphs showing the change in body weight, treadmill distance, and grip force after 6- or 12-month treatments of tamoxifen (Tam), ribitol (Rib), and a combination of tamoxifen and ribitol (Tam/Rib), low-dose raloxifene (Rai), and a combination of low-dose raloxifene and ribitol (Ral/Rib) in FKRP P448L mutant mice compared to control C57 (Cont) mice.
  • * P ⁇ 0.05 compared to untreated control.
  • the term “consisting essentially of’ as used herein should not be interpreted as equivalent to “comprising.”
  • the term “enhance” or “increase” refers to an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold and/or can be expressed in the enhancement and/or increase of a specified level and/or activity of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more.
  • inhibitor or “reduce” or grammatical variations thereof as used herein refers to a decrease or diminishment in the specified level or activity of at least about 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In particular embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).
  • a “therapeutically effective” amount as used herein is an amount that provides some improvement or benefit to the subject.
  • a “therapeutically effective” amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject (e.g., in the case of a FKRP -mutation related disease improved walking and/or gait, reduced joint stiffness, improved respiratory function, reduced incidence of a neuronal migration abnormality, enhanced glycosylation of a-DG or other cell membrane proteins, etc.).
  • a “therapeutically effective” amount is an amount that provides some improvement or benefit to the subject.
  • a “therapeutically effective” amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject (e.g., in the case of a FKRP -mutation related disease improved walking and/or gait, reduced joint stiffness, improved respiratory function, reduced incidence of a neuronal migration abnormality, enhanced glycosylation of a-DG or other cell membrane proteins, etc.
  • treat By the term “treat,” “treating,” or “treatment of’ (or grammatically equivalent terms) is meant to reduce or to at least partially improve or ameliorate the severity of the subject’s condition and/or to alleviate, mitigate or decrease in at least one clinical symptom and/or to delay the progression of the condition.
  • prevent means to delay or inhibit the onset of a disease.
  • the terms are not meant to require complete abolition of disease, and encompass any type of prophylactic treatment to reduce the incidence of the condition or delay the onset of the condition.
  • a “prevention effective” amount as used herein is an amount that is sufficient to prevent and/or delay the onset of a disease, disorder and/or clinical symptoms in a subject and/or to reduce and/or delay the severity of the onset of a disease, disorder and/or clinical symptoms in a subject relative to what would occur in the absence of the methods of the invention.
  • the level of prevention need not be complete, as long as some benefit is provided to the subject.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound.
  • One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well-known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients.
  • Exemplary pharmaceutically acceptable carriers for the compositions of this invention include, but are not limited to, phosphate buffered saline (PBS), sterile pyrogen-free water, and other sterile pyrogen-free physiological saline solutions.
  • a "pharmaceutically acceptable” component such as a salt, carrier, excipient or diluent of a composition according to the present invention is a component that (i) is compatible with the other ingredients of the composition in that it can be combined with the compositions of the present invention without rendering the composition unsuitable for its intended purpose, and (ii) is suitable for use with subjects as provided herein without undue adverse side effects (such as toxicity, irritation, and allergic response). Side effects are “undue” when their risk outweighs the benefit provided by the composition.
  • Non-limiting examples of pharmaceutically acceptable components include any of the standard pharmaceutical carriers such as saline solutions, water, emulsions such as oil/water emulsion, microemulsions and various types of wetting agents.
  • Grammatical variations of “administer,” “administration,” and “administering” to a subject include any route of introducing or delivering to a subject an agent/active compound (e.g., a ribitol and a SERM).
  • an agent/active compound e.g., a ribitol and a SERM.
  • Administration can be carried out by any suitable route, including oral, buccal (e.g., sub-lingual), topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intrajoint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intracerebroventricular, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like.
  • buccal e.g., sub-lingual
  • topical e.g., intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intrajoint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intracerebroventricular
  • the administration is oral administration.
  • Concurrent administration means that the compounds are administered at the same point in time, overlapping in time, or one following the other. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time.
  • Systemic administration refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject’s body (e.g., greater than 50% of the body), for example through entrance into the circulatory or lymph systems.
  • local administration refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount.
  • locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject's body.
  • Administration includes self-administration and the administration by another.
  • a composition of the present invention can be administered orally or intravenously or subcutaneously to a subject daily, weekly, biweekly or monthly.
  • the ribitol and/or the SERM can be administered from about every 1 hour to about every 12 hours (e.g., about every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or about every 12 hours). In some embodiments, the ribitol and/or the SERM can be administered from about every 1 week to about every 7 days (e.g., about every 1, 2, 3, 4, 5, 6, or about every 7 days). In some embodiments, the ribitol and/or the SERM can be administered from about every 1 week to about every 4 weeks (e g., about every 1, 2, 3, or about every 4 weeks). In some embodiments, the ribitol and/or the SERM can be administered from about every 1 month to about every 6 months (e.g., about every 1, 2, 3, 4, 5, or about every 6 months).
  • the method of this invention can include a step of additionally administering to the subject an additional therapeutic agent, in combination with the ribitol and the SERM (concurrently, before and/or after the ribitol and the SERM administration).
  • a therapeutic agent of this invention include a phosphodiesterase type 5 (PDE 5) inhibitor, a nonsteroidal anti-inflammatory agent, a metabolite supplement, or any combination thereof.
  • the ribitol and the SERM can be co-administered with (prior to, simultaneously and/or after) a bisphosphonate (e.g., Alendronate), an angiotensin converting enzyme inhibitor (ACE inhibitor), an angiotensin receptor blocker (e.g., rosartan), singly or in any combination.
  • a bisphosphonate e.g., Alendronate
  • ACE inhibitor an angiotensin converting enzyme inhibitor
  • an angiotensin receptor blocker e.g., rosartan
  • the ribitol and the SERM can be administered with any other therapy and/or therapeutic agent (simultaneously, before and/or after), such as steroid therapy and/or FKRP gene therapy to enhance or increase the therapeutic effect.
  • the subject of this invention is a female subject and in some embodiments, the subject of this invention is a male subject.
  • the SERM is tamoxifen and the subject is a female subject.
  • the SERM is raloxifene and the subject is a male or female subject that has or is at increased risk of having muscular dystrophy.
  • the methods of this invention can also be used to treat non-muscular dystrophy diseases for which restoration of and/or enhanced glycosylation of a-DG would be beneficial and/or therapeutic.
  • ribitol restores glycosylation, reduction of which is the cause of the diseases, while the SERMs prevent any muscle damage-related secondary inflammatory response in diseased muscles.
  • SERM also improves osteoporosis due to disuse of muscles, thus preventing bone fractures which often causes dire consequences to patients.
  • the combined treatment of ribitol and tamoxifen or raloxifene may provide preferable treatment to the FKRP mutation-related diseases.
  • tamoxifen and raloxifene were tested at doses similar to and lower than the doses currently used in clinics for treating human diseases in long-term (e.g., 12 month) animal model studies.
  • lower doses of tamoxifen and raloxifene could also provide therapeutic effect to diseased muscles of patients with FKRP mutations.
  • these two drugs can be safely applied for long-term treatment of FKRP mutation-related diseases.
  • combined treatment of ribitol with clinically applicable doses of either tamoxifen or raloxifene may be able to achieve better efficacy than any drug alone.
  • FIG. 1 shows the glycosylation that was detected with the IIH6 antibody on samples of FKRP P448L mutant mice treated for 12 months. A loss of glycosylation was seen in control tissues with high background staining most notable in the diaphragm. Ribitol treatment, but not tamoxifen alone, clearly enhanced glycosylation.
  • the combined treatment showed the most preferable preservation of histology and glycosylation with IIH6 staining homogeneously, with the pattern similar to that in normal control C57 mice.
  • a positive signal for matriglycan was barely detectable in the saline treated control in the Western blot, and no difference seen in the sample of tamoxifen and raloxifene treatments alone.
  • a marked increase in IIH6 staining was seen in the heart and TA in combination treatment groups.
  • FIG. 2 the areas of fibrosis (white grey patches) were evident in the muscles of untreated mutant mice. Ribitol treatment reduced the fibrosis, but the clearest reduction was observed in the muscles from the combined treatment.
  • H&E staining in P448L mutant mice showed that the TA of untreated control mice had clusters of centrally nucleated fibers with mononuclear cell infiltration (FIG. 4, panel A). Reduced numbers of mononuclear cells were observed in all treated TA samples. Large pockets of mononuclear cell and fat infiltration were noted in the diaphragm of untreated controls with the remaining muscle fibers sporadically isolated. An increase in the number of muscle fibers was observed in ribitol treated diaphragm due to a reduction in fibrosis and fat replacement. Mice treated with tamoxifen with and without ribitol showed improved numbers of muscle fibers but retained clear fibrosis and streaks of mononuclear cells.
  • Raloxifene with and without ribitol showed the greatest improvement in diaphragm histology with the least streaks of fibrosis and mononuclear cells.
  • FIG. 4, panel B demonstrated a reduction in centrally nucleated fibers in the TA and diaphragm in all treatment groups with combination treatments showing fewer centrally nucleated fibers than single treatment.
  • C57 controls in addition to the P448L diseased model control were used for references to evaluate the nature of changes. Almost all parameters changed towards levels seen in the C57 mice after treatments, indicating improvement.
  • Inspiratory time (Ti) was significantly reduced in tamoxifen with ribitol as well as raloxifene with and without ribitol, though not to the level of C57.
  • Expiratory time (Te) was significantly increased in the same three treatments with the combination treatment of raloxifene with ribitol reaching similar level to C57.
  • Peak inspiratory flow (PIF) was only slightly improved in the combination treatments with no change in peak expiratory flow (PEF), though raloxifene alone showed further reduction.
  • End inspiratory pause was significantly reduced in all treatment groups with only a slight reduction in end expiratory pause (EEP) in the tamoxifen and raloxifene alone treatments. EIP reduction was the most consistent feature for improvement after gene therapy, ribitol and SERM treatments. Reduced frequency (F) was seen in the combination therapies with overall minute volume (MV) being reduced in tamoxifen alone as well as raloxifene with and without ribitol. Enhanced pause (Penh) was significantly reduced in all treatment groups except ribitol, though not to the level of C57.
  • Cardiac function and morphology were examined using high-frequency ultrasound. (FIG. 9).
  • C57 controls in addition to the P448L diseased model control were used for references to evaluate the nature of changes.
  • the P448L mutant mouse showed a reduced ejection fraction and stroke volume as well as an increase in myocardial thickness compared to C57 controls, which lead to reduced cardiac output.
  • EF was increased with combination treatment tamoxifen and raloxifene compared to untreated controls with significant increase for the Raloxifene alone group.
  • myocardial thickness is reduced across all treatment groups with the biggest reduction noted in the raloxifene alone group.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions et des méthodes d'utilisation de celles-ci dans le traitement de la dystroglycanopathie, de la dystrophie musculaire et d'autres troubles. En particulier, l'invention concerne une méthode de traitement d'un trouble associé à une mutation ou une perte de fonction dans un gène de la protéine liée à la fukutine (FKRP) et/ou un trouble associé à un défaut de glycosylation de l'α-DG chez un sujet, comprenant l'administration au sujet d'une quantité efficace d'un ribitol et d'un modulateur sélectif du récepteur des œstrogènes (SERM).
PCT/US2025/022885 2024-04-04 2025-04-03 Compositions et méthodes de traitement de maladies et de troubles associés à une faiblesse musculaire Pending WO2025212841A1 (fr)

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US202463574452P 2024-04-04 2024-04-04
US63/574,452 2024-04-04
US202463632671P 2024-04-11 2024-04-11
US63/632,671 2024-04-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180207112A1 (en) * 2017-01-25 2018-07-26 The Charlotte Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Compounds and methods for treating muscular dystrophy and other disorders
US20200061092A1 (en) * 2018-08-24 2020-02-27 The Charlotte Mecklenburg Hospital Authority D/B/A Atrium Health Methods and compositions for treating disorders associated with muscle weakness
WO2022056266A2 (fr) * 2020-09-11 2022-03-17 Arrowhead Pharmaceuticals, Inc. Agents d'arni destinés à inhiber l'expression de dux4, leurs compositions et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180207112A1 (en) * 2017-01-25 2018-07-26 The Charlotte Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Compounds and methods for treating muscular dystrophy and other disorders
US20200061092A1 (en) * 2018-08-24 2020-02-27 The Charlotte Mecklenburg Hospital Authority D/B/A Atrium Health Methods and compositions for treating disorders associated with muscle weakness
WO2022056266A2 (fr) * 2020-09-11 2022-03-17 Arrowhead Pharmaceuticals, Inc. Agents d'arni destinés à inhiber l'expression de dux4, leurs compositions et leurs procédés d'utilisation

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