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WO2025215092A1 - Inhibiteurs sélectifs de hdac6 destinés à être utilisés dans le traitement de la dystrophie myotonique de type 1 - Google Patents

Inhibiteurs sélectifs de hdac6 destinés à être utilisés dans le traitement de la dystrophie myotonique de type 1

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Publication number
WO2025215092A1
WO2025215092A1 PCT/EP2025/059739 EP2025059739W WO2025215092A1 WO 2025215092 A1 WO2025215092 A1 WO 2025215092A1 EP 2025059739 W EP2025059739 W EP 2025059739W WO 2025215092 A1 WO2025215092 A1 WO 2025215092A1
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WIPO (PCT)
Prior art keywords
hdac6
treatment
cells
skeletal muscle
inhibitors
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English (en)
Inventor
Cécile MARTINAT
Noémie BERENGER-CURRIAS
Christina JACOB
Peter Sommer
Denis Furling
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.)
Ksilink
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite D'Evry Val D'Essonne
Centre d'Etude des Cellules Souches CECS
Sorbonne Universite
Original Assignee
Ksilink
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite D'Evry Val D'Essonne
Centre d'Etude des Cellules Souches CECS
Sorbonne Universite
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Application filed by Ksilink, Centre National de la Recherche Scientifique CNRS, Institut National de la Sante et de la Recherche Medicale INSERM, Universite D'Evry Val D'Essonne, Centre d'Etude des Cellules Souches CECS, Sorbonne Universite filed Critical Ksilink
Publication of WO2025215092A1 publication Critical patent/WO2025215092A1/fr
Pending legal-status Critical Current
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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

Definitions

  • the present invention is in the field of medicine, in particular genetic diseases.
  • Myotonic dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy of genetic origin, with a prevalence of 1/8,000 worldwide, and remains a disease for which there is no treatment. Management primarily includes monitoring for complications and supportive care (assistive devices, hormone therapy, pain medication). Its multisystemic symptoms, which include myotonia, muscle wasting, cardiac conduction defects, insulin resistance, cataracts, and cognitive dysfunction, are linked to disrupted regulation of alternative splicing, mRNA translation and mRNA stability that affect hundreds of genes (Du, Hongqing, et al. "Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy.” Nature structural & molecular biology 17.2 (2010): 187-193').
  • RNA-binding proteins in particular MBNL1, which is sequestered in intranuclear ribonucleoprotein aggregates (called foci) and triggered by a CTG repeat expansion in the 3 Z UTR of the DMPK (dystrophic myotonia protein kinase) gene (Kanadia, Rahul N., et al. "A muscleblind knockout model for myotonic dystrophy, "science 302.5652 (2003): 1978-1980). Accordingly, there are major ongoing efforts to identify therapeutic drugs for the treatment of DM1.
  • DMPK distrophic myotonia protein kinase
  • HDAC6 is a unique member of the histone deacetylase (HD AC) family, mainly residing in the cytoplasm and belonging to class lib HDACs. HDAC6 deacetylates several cytoplasmic substrates such as a-tubulin, cortactin and HSP90, whereas other HDACs are typically central regulators of gene expression in the cell nucleus.
  • HDAC6 inhibitors have been made to treat a variety of diseases.
  • several anticancer treatments targeting HDAC6 have been proposed (He, Xingrui, et al. "Novel selective histone deacetylase 6 (HDAC6) inhibitors: a patent review (2016-2019).
  • HDAC6 deletion or inhibition has been shown to be beneficial for some neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (Shen, Sida, and Alan P. Kozikowski. "A patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2014- 2019). " Expert opinion on therapeutic patents 30.2 (2020): 121-136). More recently, the pharmacological inhibition of HDAC6 was shown to improve muscle phenotypes in dystrophin-deficient mice (Osseni, Alexis, et al. "Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-fi via Smad3 acetylation.” Nature Communications 13.1 (2022): 7108).
  • Vorinostat improves DM1 splicing abnormalities in DM1 muscle cell lines and skeletal muscle from a DM1 mouse model (Neault, Nafisa, et al. "Vorinostat improves myotonic dystrophy type 1 splicing abnormalities in DM1 muscle cell lines and skeletal muscle from a DM1 mouse model. "International Journal of Molecular Sciences 24.4 (2023): 3794).
  • the present invention is defined by the claims.
  • the present invention relates to the use of selective HDAC6 inhibitors for the treatment of myotonic dystrophy type 1.
  • myotonic dystrophy type 1 or “DM1” has its general meaning in the art and refers to a rare genetic multi-system disorder characterized by a wide range of muscle-related manifestations (muscle weakness, myotonia, early onset cataracts (before age 50) and systemic manifestations (cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immunologic involvement) that vary depending on the age of onset.
  • muscle weakness muscle weakness, myotonia, early onset cataracts (before age 50)
  • systemic manifestations cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immunologic involvement
  • the very wide clinical spectrum ranges from lethal presentations in infancy to mild, late-onset disease.
  • the term is also known as “Steinert myotonic dystrophy”. Diagnosis is suspected on the characteristic clinical manifestations and a consistent family history and confirmed by molecular genetic testing of the causative gene expansion.
  • the term "patient” refers to a warm-blooded animal, preferably a mammal (including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc...), and more preferably a human.
  • the patient is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure, or is monitored for the development of a disease.
  • the patient is an adult (for example a subject above the age of 18).
  • the patient is a child (for example a subject below the age of 18).
  • the patient is a male.
  • the patient is a female.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • the term "therapeutically effective amount” is meant a sufficient amount of the active ingredient for treating or reducing the symptoms at reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the active ingredients; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • composition refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients.
  • the pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier.
  • Class I HDACs which include HDAC1, HDAC2, HDAC3, and HDAC8, are related to the yeast RPD3 gene.
  • Class II HDACs which include HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HD AC 10, are related to the yeast Hdal gene.
  • Class III HDACs which are also known as the sirtuins are related to the Sir2 gene and include SIRT1-7.
  • Class IV HDACs which contains only HDAC11, has features of both Class I and II HDACs.
  • the term “inhibitor” refers to a compound that decreases the magnitude of at least one activity, signaling or expression of a molecule (e.g. HDAC6) compared to the magnitude of the activity, signaling or expression observed in the absence of the inhibitor. In some instances, an inhibitor will substantially decrease the magnitude of at least one activity, signaling or expression of a molecule compared to the magnitude of the activity or expression observed in the absence of the inhibitor. In some instances, an inhibitor will completely diminish the magnitude of at least one activity, signaling or expression of a molecule compared to the magnitude of the activity, signaling or expression observed in the absence of the inhibitor. Certain exemplary inhibitors include, but are not limited to, proteins, peptides, antibodies, peptibodies, aptamers, antisense oligonucleotides, interfering RNA, carbohydrates or small organic molecules.
  • selective HDAC6 inhibitor means that the compound inhibits the activity or expression of HDAC6.
  • a selective HDAC6 inhibitor inhibits the activity or expressions of HDAC6 to a substantially greater extent, such as 5x, 10x, 15x, 20x greater or more, than to any other type of HD AC enzyme, such as HDAC1 or HDAC2.
  • the selectivity ratio of HDAC6 over HDAC1 is from about 5 to about 30,0000, e.g., about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 1000, about 2000, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000, about 9000, about 10,000, about 15,000, about 20,000, about 25,000, or about 30,000, including all values and ranges therebetween.
  • a HDAC6 inhibitor may be at least 100-fold selective against HDAC6 compared to all other isozymes of HD AC.
  • selectivity may be determined by reference of another HD AC inhibitor, such as a pan-HDAC inhibitor — that is an inhibitor that inhibits HDACs other than HDAC6 in addition to HDAC6.
  • a pan-HDAC inhibitor is an inhibitor that inhibits HDACs other than HDAC6 in addition to HDAC6.
  • Givinostat is an example of a pan- HD AC inhibitor.
  • a selective HDAC6 inhibitor inhibits HDACs other than HDAC6 at least 100-fold less effectively than givinostat.
  • the present invention relates to a method of treating myotonic dystrophy type 1 (DM1) in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a selective HDAC6 inhibitor.
  • DM1 myotonic dystrophy type 1
  • the HDAC6 inhibitor of the present invention is a selective HDAC6 inhibitor.
  • pan-HDAC inhibitors e.g. vorinostat
  • HDAC6 selective oxidative deposition
  • a person of skill in the art can identify which analogs of the compound have selective HDAC6 activity.
  • illustrative HDAC6 inhibitors are provided in:
  • HDAC6 Histone Deacetylase 6
  • the HDAC6 inhibitor is a fluoroalkyl-oxadiazole derivative.
  • Illustrative fluoroalkyl-oxadiazole derivatives that may be used as HDAC6 inhibitors include those described herein and those described in Int’l Pat. Appl. No. PCT/US2020/066439, published as WO2021127643A1 the content of which is incorporated by reference herein in its entirety.
  • PCT/US2020/066439 published as WO2021127643A1, also describes methods of synthesis of such compounds, which are specifically incorporated by reference herein.
  • the HDAC6 inhibitor is CAY10603, tubacin, ricolinostat (ACY- 1215), citarinostat (ACY-241), ACY-738, QTX-125, CKD-506, nexturastat A, tubastatin A, or HPOB, or an analog thereof.
  • the drugs herein disclosed are combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 The effect of HDAC6 inhibitors were screened in vitro on the fusion of DM1 and SMA immortalized skeletal muscle cells.
  • Figure 2 HDAC6 inhibitors normalize the fusion defect of in vitro DM1 hiPSC-derived skeletal muscle cells.
  • B Quantification of Fusion Area index of hiPSCs derived myotubes treated with HDAC6 inhibitors. Data represent the mean ⁇ SD of fusion area Index calculated over four individual technical replicates (histogram, left axis). The normalized cell viability is also indicated (curve, right axis).
  • Statistics were calculated using an ordinary two-ways ANOVA tests * : p-values ⁇ 0.05.
  • FIG. 3 HDAC6 inhibitors reduce the number of nuclear foci in DM1 hiPSC-derived skeletal muscle cells.
  • A Scheme of foci quantification in differentiating hiPSCs-derived skeletal muscle cells protocol.
  • B Representative images of the mask used to quantify foci of mutant DMPK mRNA detected by fluorescent in situ hybridization in nuclei of differentiating hiPSCs-derived skeletal muscle cells untreated and treated with HDAC6 inhibitors. Nuclei, detected by Hoescht staining, are represented as their outlines.
  • C Quantification of the number of foci per nuclei of differentiating hiPSCs-derived skeletal muscle cells treated with HDAC6 inhibitors.
  • SD Standard Deviation
  • HDAC6 inhibitors reduce the expression of DMPK mRNA and normalize alternative splicing defect in DM1 hiPSC-derived skeletal muscle cells.
  • D Quantification exon 11 in ISR1 mRNA in differentiating hiPSC-derived skeletal muscle cells treated with HDAC6 inhibitors.
  • Quantification of SMAD3 acetylated and phosphorylated in nuclei of differentiating hiPSC-derived skeletal muscle cells represent the average of fluorescence intensity of phospho-SMAD3 (curve labelled 2, right axis) and acetyl-SMAD3 (curve labelled 1, left axis) immunostaning in nuclei of hiPSCs- derived skeletal muscle cells ⁇ SD for four technical replicates.
  • Figure 6 Inhibition of HDAC6 normalize the fusion defect and reduce the number of nuclear foci of in vitro DM1 hiPSC-derived skeletal myotubes.
  • A Scheme of fusion and foci quantification in advanced differentiating hiPSCs-derived skeletal muscle cells protocol.
  • B Quantification of Fusion Area index of hiPSCs derived myotubes treated with HDAC6 inhibitors. Data represent the mean ⁇ SD of fusion area index calculated over four individual technical replicates. The normalized cell viability, quantified as the total nuclei area , is also indicated (curve, right axis). Statistics were calculated using an ordinary two-ways ANOVA tests * : p-values ⁇ 0.05, only conditions with cell viability > 60% were considered.
  • Figure 7 Inhibition of HDAC6 reduce the number of nuclear foci and the expression of DMPK mRNA and normalize alternative splicing defect in in vitro DM1 hiPSC-derived skeletal myotubes.
  • A Scheme of fusion and foci quantification in advanced differentiating hiPSCs-derived skeletal muscle cells protocol.
  • B Quantification of the number of foci per nuclei in hiPSCs derived myotubes treated with HDAC6 inhibitors. Data represent the mean ⁇ SD of the number of foci per nuclei, calculated over four individual technical replicates. The normalized cell viability is plotted as a curve (right axis).
  • C C.
  • Human iPSC were generated by reprogramming skin fibroblasts derived from non-affected and DM1 affected patients as previously described 1 .
  • the repeats expansion length was estimated to be approximately -2500 CTG repeats 1 .
  • Informed consents were obtained from all the patients included in this study, complying with the ethical guidelines of the institutions and with the legislation requirements. All the different hiPSC lines were grown on culture dishes coated with vitronectine (Gibco) and maintained in iPS-Brew XF medium (Miltenyi Biotec). Cell passaging was performed using accutase (Life Technologic) every 5 days and culture medium was changed every 2 days as previously described 1 .
  • Myoblasts were derived from hiPSCs using the STEMdiffTM Myogenic Progenitor Supplement Kit (STEMCELL technologies). Briefly, hiPSCs were seeded at different densities on Matrigel (Corning), in iPS-Brew XF medium (Miltenyi Biotec) supplemented with lOpM Y-27632 (BioTechne) and grown for 24h at 37 °C, 5% CO2. The densities resulting in the recommended confluency of 30% with colonies of 10 to 30 cells were selected to pursue differentiation. The cells were kept in culture for 30 days, in DMEM/F12 without HEPES medium (ThermoFisher Scientific) complemented with the different supplements of the kit. Medium was changed every day.
  • DMEM/F12 without HEPES medium ThermoFisher Scientific
  • Myoblasts weree expanded and frozen for banking in expansion medium [DMEM with lOOOmg/L D-Glucose (STEMCELL technologies) supplemented with MyoCultTM-SF Expansion Supplement Kit (STEMCELL technologies)]. Their myogenic identity was assessed by myogenic markers immunostaining (Desmin, PAX7, MF20, MyoD, MyoG, Table 1).
  • hiPSC s-derived myoblasts cells were seeded between 15 000 and 25 000 cells per cm 2 on Matrigel (Coming) and let grown for 72h, in expansion medium at 37 °C, 5% CO2. When the cells reached a confluency of 80 to 90%, medium was switched into the MyoCultTM Differentiation Kit (Human) (STEMCELL technologies) and the cells were grown for 7 more days minimum, with medium refreshment every 3 to 4 days. The fusion of myotubes was assessed by Desmin and MF20 immunostaining.
  • Immortalized myoblasts were expanded on gelatin coating (Sigma), in immortalized expansion medium DMEM+GlutaMAX medium (Life Technologic) supplemented with 16% of Medium 199 + GlutaMAX (Life Technologic), 20% FBS (Life Technologic), 25pg/mL of fetuin (ThermoFisher Scientific), 5pg/mL of insulin solution human (Sigma), 0.2pg/mL of dexamethasone (Sigma), 5 ng/mL of EGF human recombinant protein (Life Technologic), 0.5 ng/mL of bFGF human recombinant protein (Life Technologic), and 1 pM of penicillin/streptomycin (Life Technologic).
  • DMEM+GlutaMAX medium (Life Technologic) supplemented with 16% of Medium 199 + GlutaMAX (Life Technologic), 20% FBS (Life Technologic), 25pg/mL of fetuin (ThermoFisher Scientific), 5
  • myoblasts were seeded at 100 000 cells per cm 2 on collagen I coating (Gibco), in immortalized expansion medium and let grown for 24h.
  • collagen I coating Gibco
  • To induce myogenic fusion cells were shifted in DMEM+GlutaMAX medium supplemented with 10 pg/mL of insulin solution human and 1 pM of penicillin/streptomycin, for 7 days minimum. The fusion of myotubes was assessed by Desmin and MF20 immunostaining.
  • Immortalized myoblasts were seeded as previously described for myogenic differentiation, in immortalized myoblasts expansion medium at 37 °C, 5% CO2. Cells were switched in differentiation medium after 24h. Chemical compounds were added at one day later at 8 different concentrations ranging from 0.01 pM to 10 pM. Each chemical compound was dissolved in pure DMSO for which the final concentration was calculated to not exceed 0.1%.
  • Immortalized myoblasts were seeded as previously described for myogenic differentiation, in immortalized myoblasts expansion medium at 37 °C, 5% CO2. Cells were switched in differentiation medium after 24h. The compounds, dissolved in pure DMSO (MilliporeSigma), were added to the immortalized myotubes differentiation medium after 24h. The final concentration of DMSO did not exceed 0.1% and a solution of 0.1% DMSO was used as a negative control. Differentiation medium was refreshed after 3 days of treatment. After 7 days of treatment, the fusion was assessed by immunostaining of MF20. hiPCS-derived myoblasts were seeded as previously described for myogenic differentiation, and let grown for 72h, in expansion medium at 37 °C, 5% CO2.
  • the defects were quantified using the flanking set as reference.
  • the 18S housekeeping gene was used as reference gene. Fold change variations induced by compound treatments were calculated using the 2-AACt method with DMSO treated control cells as reference.
  • FISH Fluorescent in situ hybridization
  • Toxic mRNA foci were quantified with FISH in differentiating hiPSC-derived myoblasts treated in 384-well plates. FISH experiments were performed as previously described 3 . Briefly, cells were fixed after 48h of treatment with 4% PF A (Electron Microscopy Sciences) for 10 min at RT, and washed with PBS. Cells were then incubated overnight at 4 °C with 70% Ethanol. Cells were re-hydrated for lOmin at RT, with PBS supplemented with 5mM of MgC12.
  • Myotonic Dystrophy type 1 (DM1) is an inherited disease characterized by multi-systemic symptoms, particularly in skeletal muscles (progressive weakness and atrophy, myotonia).
  • DM1 myotonic Dystrophy type 1
  • DM1 immortalized myoblasts were differentiated for eight days with the addition of each compound at the start of the differentiation process.
  • Figure 1A Bioactive compounds
  • DM1 related molecular hallmark is the presence of nuclear aggregates made of toxic DMPK mRNAs called foci 8, 9 .
  • HDAC6i were affecting those aggregates
  • hiPCS-derived skeletal muscle cells were treated with the five selected HDAC6i and observed after 48h of treatment ( Figure 3A). Only conditions maintaining at least 60% of cell viability were considered.
  • Figure 3B-C a significate reduction of nuclear foci was observed after treatment with HDAC6i ( Figure 3B-C), up to more than 50%.
  • the compounds improved the myogenic fusion and reduced the number of nuclear foci at the same micromolar range concentrations.
  • DMPK mRNA in hiPCS-derived skeletal muscle cells treated with three HDAC6i ISOX, Tubastatin A, Citarinostat, Figure 4A.
  • DM1 cells treated with these compounds displayed a significant reduction of DMPK mRNA when compared to mock-treated cultures ( Figure 4B), correlating with the reduced number of nuclear foci.
  • the pathogenesis of DM1 involves an RNA gain-of-function mechanism caused by the expression of mutant mRNAs containing abnormal expansion of hundreds to thousands of CUG repeats.
  • HDAC6 is a unique cytoplasmic member of the histone deacetylase family. It has been recently demonstrated that SMAD3 is a new target of HDAC6 and that inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by SMAD3 acetylation 13 . We therefor sought to evaluate whether a similar mechanism could be involved in DM1 skeletal muscle cells. The proportions of acetylated and phosphorylated SMAD3 were quantified in nuclei of DM1 hiPCS-derived skeletal muscle cells treated or not with the five HDAC6i (Figure 5). Our results confirmed that the treatment with these five HDAC6i led to an increased proportion of acetylated-SMAD3 that is negatively correlated with a decrease of phophorylated-SMAD3.

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Abstract

La dystrophie myotonique de type 1 (DM1) est une maladie héritée caractérisée par des symptômes multi-systémiques, en particulier dans les muscles squelettiques (faiblesse progressive et atrophie, myotonie). Les inventeurs ont criblé 7 500 composés bioactifs pour déterminer leur capacité à améliorer la fusion myogénique et à réduire les marques moléculaires de cellules musculaires squelettiques de la DM1. Les inventeurs ont découvert que cinq composés, tous inhibant la HDAC6, une histone désacétylase cytoplasmique, étaient efficaces, dans la gamme micromolaire, pour normaliser la fusion myogénique, réduire le nombre de foyers nucléaires d'ARNm mutant du DMPK, diminuer le niveau d'expression de l'ARNm du DMPK, restaurer l'épissage de plusieurs gènes, et augmenter l'acétylation du SMAD3, un facteur de transcription intervenant dans le développement musculaire. Les effets des inhibiteurs de HDAC6 ont été observés à la fois dans des cellules musculaires squelettiques immortalisées et dérivées de hiPSC provenant de patients atteints de DM1, et à différents stades de différenciation. Ainsi, la présente invention concerne l'utilisation d'inhibiteurs sélectifs de HDAC6 pour le traitement de la DM1.
PCT/EP2025/059739 2024-04-10 2025-04-09 Inhibiteurs sélectifs de hdac6 destinés à être utilisés dans le traitement de la dystrophie myotonique de type 1 Pending WO2025215092A1 (fr)

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