WO2025257151A1 - Méthodes et composition pharmaceutique pour le traitement de ciliopathies - Google Patents

Méthodes et composition pharmaceutique pour le traitement de ciliopathies

Info

Publication number
WO2025257151A1
WO2025257151A1 PCT/EP2025/066063 EP2025066063W WO2025257151A1 WO 2025257151 A1 WO2025257151 A1 WO 2025257151A1 EP 2025066063 W EP2025066063 W EP 2025066063W WO 2025257151 A1 WO2025257151 A1 WO 2025257151A1
Authority
WO
WIPO (PCT)
Prior art keywords
cb1r
ciliopathies
inhibitor
treatment
subject
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/EP2025/066063
Other languages
English (en)
Inventor
Hélène FRANCOIS
Remy PIEDAGNEL
Brigitte LELONGT
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.)
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Sorbonne Universite
Original Assignee
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Sorbonne Universite
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 Assistance Publique Hopitaux de Paris APHP, Institut National de la Sante et de la Recherche Medicale INSERM, Sorbonne Universite filed Critical Assistance Publique Hopitaux de Paris APHP
Publication of WO2025257151A1 publication Critical patent/WO2025257151A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the invention is in the field of nephrology, more particularly, provides method and pharmaceutical composition to treat renal ciliopathies.
  • CKD Chronic kidney disease
  • RAS renin angiotensin system
  • TGFpi TGFpi
  • Renal ciliopathies including autosomal dominant polycystic kidney disease (ADPKD), recessive polycystic kidney disease and nephronophthisis are mostly caused by gene mutations impairing the primary cilium function in renal tubular cells.
  • ADPKD autosomal dominant polycystic kidney disease
  • recessive polycystic kidney disease and nephronophthisis are mostly caused by gene mutations impairing the primary cilium function in renal tubular cells.
  • Clinical renal presentation involves the development of cysts and renal fibrosis progressively leading to end stage renal disease at various ages depending on the mutation type (3).
  • CB1 cannabinoid receptor 1
  • the invention relates to a method for treating ciliopathies comprising a step of administering an inhibitor of Cannabinoid receptor 1 (CB1R) in a subject in need thereof.
  • CBD1R Cannabinoid receptor 1
  • CB1 inhibition (genetic invalidation or using a pharmacological peripheral blockade) reduces CKD and fibrosis in the severe renal ischemia reperfusion model, which represent an example of AKI to CKD transition, a common problem in patients. Therefore, CB1 inhibition represents an important therapeutic strategy in CKD, regardless of the cause.
  • the invention relates to a method for treating ciliopathies comprising a step of administering an inhibitor of Cannabinoid receptor 1 (CB1R) in a subject in need thereof.
  • CBD1R Cannabinoid receptor 1
  • the invention relates to an inhibitor of Cannabinoid receptor 1 (CB1R) for use in the treatment of ciliopathies in a subject in need thereof.
  • CBD1R Cannabinoid receptor 1
  • the invention relates to an inhibitor of Cannabinoid 1 (CB1) for use in the treatment of ciliopathies in a subject in need thereof.
  • CBD1 Cannabinoid 1
  • the ciliopathies is Autosomal dominant polycystic kidney disease or “ADPKD”.
  • ADPKD is a polycystic kidney disease caused by one or more genetic mutations in the PKD1 and/or PKD2 gene. 85% of ADPKD is caused by mutations in PKD1, which is located on chromosome 16, with the majority of the remaining ADPKD cases caused by mutations in PKD2, which is located on chromosome 4.
  • the ciliopathies is nephronophthisis (NPHP).
  • NPHP nephronophthisis
  • Nephronophthisis is an autosomal recessive cystic kidney disease that is a frequent cause of ESRD in children.
  • NPHP is characterized by kidneys of normal or reduced size, cysts concentrated at the corticomedullary junction, and tubulointerstitial fibrosis. Mutations in one of several NPHP genes, for example, NPHP1, have been identified in patients with NPHP.
  • the term “subject” refers to any mammals, such as a rodent, a feline, a canine, and a primate. Particularly, in the present invention, the subject is a human afflicted with or susceptible to be afflicted with at least one of renal ciliopathies as described above.
  • the subject is a human afflicted with or susceptible to be afflicted with nephronophthisis (NPHP)
  • the subject is a human afflicted with or susceptible to be afflicted with Joubert syndrome and related disorders (JSRD).
  • JSRD includes a broad range of hallmark features, including brain, retinal, and skeletal abnormalities. Certain subjects with JSRD have polycystic kidney disease, in addition to hallmark features of JSRD.
  • the subject is a human afflicted with or susceptible to be afflicted with Bardet-Biedl syndrome (BBS).
  • BBS Bardet-Biedl syndrome
  • a hallmark feature of BBS is the presence of renal cysts.
  • Cannabinoid refers to several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. Cannabidiol (CBD) is a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. Two known cannabinoid receptors are termed CB1 and CB2.
  • the naturally occurring human CB1R gene has a nucleotide sequence as shown in Genbank Accession numbers: NM_001160226, NM_001160258, NM_001160259, NM_001160260 and NM_016083 and the naturally occurring human CB1R protein has an amino acid sequence as shown in Genbank Accession numbers NP 001153698, NP_001153730, NP_001153731, NP_057167 and NP_149421.
  • the term “inhibitor of Cannabinoid receptor 1” refers to a natural or synthetic compound that has a biological effect to inhibit the activity or the expression of CB 1R. More particularly, such compound by inhibiting CB1R activity increases the length of cilia. More particularly, such compound restores normal cilia length and function in kidneys.
  • the inhibitor of Cannabinoid receptor 1 is selected from the group consisting of but not limited to: a peptide, peptidomimetic, small organic molecule, antibody, aptamers, siRNA or antisense oligonucleotide.
  • the inhibitor of CB1R is a small organic molecule.
  • small organic molecule refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e.g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.
  • the inhibitor of CB1R is selected from the group consisting ofbut not limited to: INV-202, JD5037, AM6545, TM38837, JM-00266, JM-00252.
  • the inhibitor of CB1R is JD5037.
  • JD5037 is a compound well known in the art and it is a Peripheral CB1R Inverse Agonist. It is described Jospeh Tam et al 2012 (doi: 10.1016/j.cmet.2012.07.002) and in W02014/078309.
  • the inhibitor of CB1R expression is a short hairpin RNA (shRNA), a small interfering RNA (siRNA) or an antisense oligonucleotide which inhibits the expression of CB1R.
  • the inhibitor of CB1R expression is siRNA.
  • a short hairpin RNA (shRNA) is a sequence of RNA that makes a tight hairpin turn that can be used to silence gene expression via RNA interference.
  • shRNA is generally expressed using a vector introduced into cells, wherein the vector utilizes the U6 promoter to ensure that the shRNA is always expressed. This vector is usually passed on to daughter cells, allowing the gene silencing to be inherited.
  • Anti-sense oligonucleotides include anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of the targeted mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of the targeted protein, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence can be synthesized, e.g., by conventional phosphodiester techniques. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos.
  • Antisense oligonucleotides, siRNAs, shRNAs of the invention may be delivered in vivo alone or in association with a vector.
  • a “vector” is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically mast cells.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • adenovirus adeno-associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses Epstein-Barr viruses
  • papilloma viruses herpes virus
  • vaccinia virus
  • the inhibitor of CB1R expression is an endonuclease.
  • sequencing technologies have provided an unprecedentedly detailed overview of the multiple genetic aberrations in ciliopathies.
  • these new data strongly emphasize the need of fast and reliable strategies to characterize the normal and pathological function of these genes and assess their role, in particular as driving factors during oncogenesis.
  • the new technologies provide the means to recreate the actual mutations observed in ciliopathies through direct manipulation of the genome. Indeed, natural and engineered nuclease enzymes have attracted considerable attention in the recent years.
  • NHEJ error prone nonhomologous end-joining
  • HDR high-fidelity homology-directed repair
  • the endonuclease is CRISPR-cas.
  • CRISPR-cas has its general meaning in the art and refers to clustered regularly interspaced short palindromic repeats associated which are the segments of prokaryotic DNA containing short repetitions of base sequences.
  • the endonuclease is CRISPR-cas9 which is from Streptococcus pyogenes.
  • the CRISPR/Cas9 system has been described in U.S. Pat. No. 8,697,359 Bl and US 2014/0068797.
  • CRISPR has been recently engineered into a new powerful tool for genome editing. It has already been successfully used to target important genes in many cell lines and organisms, including human (Mali et al., 2013, Science, Vol. 339: 823-826), bacteria (Fabre et al., 2014, PLoS Negl. Trop. Dis., Vol.
  • the endonuclease is CRISPR-Cpfl which is the more recently characterized CRISPR from Provotella and Francisella 1 (Cpfl) in Zetsche et al. (“Cpfl is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13).
  • the inhibitor of CB1R is an antibody.
  • antibody is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
  • the term includes antibody fragments that comprise an antigen binding domain such as Fab z , Fab, F(ab z )2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc- diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP (“small modular immunopharmaceutical” scFv-Fc dimer; DART (ds-stabilized diabody “Dual Affinity ReTar
  • Antibodies can be fragmented using conventional techniques. For example, F(ab z )2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab z )2 fragment can be treated to reduce disulfide bridges to produce Fab z fragments. Papain digestion can lead to the formation of Fab fragments.
  • Fab, Fab z and F(ab z )2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al., 2006; Holliger & Hudson, 2005; Le Gall et al., 2004; Reff & Heard, 2001; Reiter et al., 1996; and Young et al., 1995 further describe and enable the production of effective antibody fragments.
  • the antibody is a “chimeric” antibody as described in U.S. Pat. No. 4,816,567.
  • the antibody is a humanized antibody, such as described U.S. Pat. Nos. 6,982,321 and 7,087,409.
  • the antibody is a human antibody.
  • a “human antibody” such as described in U.S. Pat. Nos. 6,075,181 and 6,150,584.
  • the antibody is a single domain antibody such as described in EP 0 368 684, WO 06/030220 and WO 06/003388.
  • the inhibitor is a monoclonal antibody.
  • Monoclonal antibodies can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Techniques for production and isolation include but are not limited to the hybridoma technique, the human B-cell hybridoma technique and the EBV-hybridoma technique.
  • the inhibitor is an intrabody having specificity for CB1R.
  • intrabody generally refer to an intracellular antibody or antibody fragment.
  • Antibodies in particular single chain variable antibody fragments (scFv), can be modified for intracellular localization. Such modification may entail for example, the fusion to a stable intracellular protein, such as, e.g., maltose binding protein, or the addition of intracellular trafficking/localization peptide sequences, such as, e.g., the endoplasmic reticulum retention.
  • the intrabody is a single domain antibody.
  • the antibody according to the invention is a single domain antibody.
  • single domain antibody sdAb or “VHH” refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such VHH are also called “Nanobody®”. According to the invention, sdAb can particularly be llama sdAb.
  • the invention relates to an inhibitor of CB1R, and ii) a classical treatment as a combined preparation for simultaneous, separate or sequential use in the treatment of ciliopathies in a subject in need thereof.
  • the terms “combined treatment”, “combined therapy” or “therapy combination” refer to a treatment that uses more than one medication.
  • the combined therapy may be a bi-therapy.
  • the combined therapy may be a tri-therapy.
  • the term “administration simultaneously” refers to administration of at least 2 or 3 active ingredients by the same route and at the same time or at substantially the same time.
  • the term “administration separately” refers to an administration of at least 2 or 3 active ingredients at the same time or at substantially the same time by different routes.
  • administration sequentially refers to an administration of at least 2 or 3 active ingredients at different times, the administration route being identical or different.
  • the term “classical treatment” refers to treatments well known in the art and used to treat a ciliopathies.
  • the classical treatment refers to Tolvaptan, Lixivaptan, metformin, Statins, mTOR inhibitor, Somatostatin and somatostatin analogs, Nephrectomy, Curcumin.
  • HMG-CoA reductase inhibitor refers to a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease.
  • HMG-CoA reductase (3 -hydroxy-3 -methylglutaryl coenzyme A reductase) is involved in the synthesis of mevalonate, a naturally occurring substance that is used by the body to make sterols, including cholesterol.
  • Statins are well know in the art, for example the following stating can be used in the context of the invention: Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin.
  • mTOR refers to mammalian target of rapamycin, kinase that in humans is encoded by the mTOR gene.
  • mTOR is a member of the phosphatidylinositol 3- kinase-related kinase family of protein kinases (PI3K).
  • the naturally occurring human mTOR gene has a nucleotide sequence as shown in Genbank Accession number NM 004958.3 and the naturally occurring human mTOR protein has an aminoacid sequence as shown in Genbank Accession number NP 004949.1.
  • the murine nucleotide and amino acid sequences have also been described (Genbank Accession numbers NM_020009.2 and NP_064393.2).
  • mTOR is involved in different pathways, including insulin, growth factors (such as IGF-1 and IGF -2), and amino acids, cellular nutrient, oxygen, and energy levels.
  • mTOR inhibitors refers to a class of drugs that inhibit mTOR. mTOR inhibitors inhibits cellular metabolism, growth, proliferation, and the formation and signaling through two protein complexes, mTORCl and mTORC2. mTOR inhibitors are well known in the art.
  • mTOR inhibitor is selected from the group consisting of but not limited to: rapamycin and rapalogs (sirolimus; temsirolimus; everolimus; deforolimus); vincristine; dactolisib or BEZ235 (phase I/II of clinical trial; Novartis); or sapanisertib (phase II of clinical trial; NCI).
  • the mTOR inhibitor is rapamycin.
  • the mTOR inhibitor is everolimus.
  • the invention relates to an inhibitor of CB1R, ii) a classical treatment, and iii) a classical nephroprotection strategies as a combined preparation for simultaneous, separate or sequential use in the treatment of kidney disease in a subject in need thereof.
  • classical nephroprotection strategies refers to control of blood pressure with ACE or ARBs, low protein and sodium diet, avoidance of nephrotoxic medications, control of cardiovascular risk factors.
  • the invention relates to an inhibitor of CB1R, and ii) a Tolvaptan as a combined preparation for simultaneous, separate or sequential use in the treatment of ciliopathies in a subject in need thereof.
  • the invention relates to an inhibitor of CB 1R, ii) a Tolvaptan and iii) classical nephroprotection strategies as a combined preparation for simultaneous, separate or sequential use in the treatment of ciliopathies in a subject in need thereof.
  • inhibitors of CB1R as described above may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising inhibitors of CB1R and pharmaceutically acceptable excipients.
  • the invention relates to pharmaceutical composition
  • pharmaceutical composition comprising an inhibitor of CB1R, and a classical treatment and a pharmaceutically acceptable excipient.
  • the invention relates to pharmaceutical composition comprising an inhibitor of CB1R and a classical treatment and a pharmaceutically acceptable excipient. In some embodiments, the invention relates to pharmaceutical composition comprising an inhibitor of CB1R, a classical nephroprotection strategies, a classical treatment and a pharmaceutically acceptable excipient.
  • the invention relates to pharmaceutical composition according to the invention, for use in the treatment of ciliopathies in a subject in need thereof.
  • the inhibitor of CB1R is compound INV-202.
  • the inhibitor of CB1R is compound JD5037.
  • the terms “pharmaceutically” or “pharmaceutically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • 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 pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • 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.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
  • dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the polypeptide (or nucleic acid encoding thereof) can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • 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.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuumdrying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • a further object of the present invention relates to a method of screening a drug suitable for the treatment of ciliopathies comprising i) providing a test compound and ii) determining the ability of said test compound to inhibit the activity and/or expression of CB1R.
  • the assay first comprises determining the ability of the test compound to bind to CB1R.
  • a population of cells is then contacted and activated so as to determine the ability of the test compound to inhibit the activity of CB1R.
  • the effect triggered by the test compound is determined relative to that of a population of immune cells incubated in parallel in the absence of the test compound or in the presence of a control agent either of which is analogous to a negative control condition.
  • control substance refers a molecule that is inert or has no activity relating to an ability to modulate a biological activity or expression. It is to be understood that test compounds capable of inhibiting the activity of CB1R, as determined using in vitro methods described herein, are likely to exhibit similar modulatory capacity in applications in vivo.
  • the test compound is selected from the group consisting of peptides, peptidomimetics, small organic molecules, aptamers or nucleic acids.
  • test compound according to the invention may be selected from a library of compounds previously synthesised, or a library of compounds for which the structure is determined in a database, or from a library of compounds that have been synthesised de novo.
  • the test compound may be selected form small organic molecules.
  • FIGURES
  • FIGURE 1 Cnrl gene expression is increased in Jck homozygous mice kidneys compared to littermate controls. Relative quantification of Cnrl (encoding CB1), Acta 2 (encoding aSMA) and TGFB induced (a target gene of active TGFB) in 12 weeks old Jck/Jck mice kidney are significantly increased compared to control littermates.
  • FIGURE 2 CB1 inhibition using JD5037 significantly increases MDCK cilia length.
  • FIGURE 3 CB1 pharmacological inhibition with JD5037 confers protection in the polycystic kidney disease (PKD) model.
  • PPD polycystic kidney disease
  • Renal ciliopathy model jck mice
  • mice carrying the jck mutation will be rederived from frozen male gametes in our animal facility and homozygous mice carrying the jck mutation and WT controls will be used for experiments. There is a rapid progression of the disease in homozygous jck/jck homozygous mice with a life span 6 months (18). However, tubular cysts are detected in newborn mice. Mice will be housed in EOPS animal facility with free access to food and tap water with a 12h- day/night cycle.
  • Vehicle with JD5037 administration at 5 mg/kg/day by daily gavage (n 10).
  • Gavage or pellets with drug
  • GFR Serum creatinine measured GFR (after Sinistrin injection) will be performed at DO and at sacrifice.
  • renal histology will be assessed in a blinded manner (Sirius Red staining with a morphometry software as we previously published (6,7) and Masson’s tri chrome).
  • We will also quantify inflammation (F4/80, CD3 markers), myofibroblasts infiltration (a-SMA infiltration) with immunohistochemistry using a quantitative morphometry software.
  • MDCK cell line that is known to bear long primary cilia and to develop cysts when they are grown in 3 D in matrix Matrigel or type I collagen gels (15) and compare cilia length and function, cyst diameters in cell grown in absence or presence of JD5037 (100 ng/ml, as performed in our primary experiment.
  • Jck mice a model of Juvenile cystic kidney disease closely resembling ADPKD in mice (9).
  • the phenotype is due to a mutation in Nek8.
  • NEK8 is localized in primary cilia and mutation in the gene induce a nephronophthisis in humans.
  • CB1 gene expression was 5 to 10-fold higher in kidneys from Jck homozygous mice compared to control mice ( Figure 1).
  • they also found a very significant increase in acta 2 expression encoding a- smooth muscle actin, a marker of activated myofibroblasts
  • TGFP-induced expression in Jck kidneys compared to controls
  • CB1 overexpression is seen in various ciliopathy models and is an important player in cystogenesis.
  • ANSK6 tubular cells forming the cysts have a shorter cilia length associated to the renal phenotype (12).
  • primary cilia length is also altered during various mutations leading to ciliopathies and nephronophthisis (13)
  • ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet, aout 2013;45(8):951-6.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les inventeurs ont découvert que l'inhibition de CB1 (par invalidation génétique ou à l'aide d'un blocage périphérique pharmacologique) réduit la MKR et la fibrose dans le modèle d'ischémie-reperfusion rénale sévère, qui représente un exemple de transition IRA vers MKR, un problème commun chez des patients. Par conséquent, l'inhibition de CB1 représente une stratégie thérapeutique importante pour la MKR, indépendamment de sa cause. Les inventeurs ont effectué des expériences préliminaires qui démontrent que l'inhibition de CB1 représente une cible entièrement nouvelle au cours de ciliopathies. En conséquence, la présente invention concerne une méthode de traitement de ciliopathies comprenant une étape d'administration d'un inhibiteur du récepteur cannabinoïde 1 (CB1R) chez un sujet en ayant besoin.
PCT/EP2025/066063 2024-06-10 2025-06-10 Méthodes et composition pharmaceutique pour le traitement de ciliopathies Pending WO2025257151A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24305911.0 2024-06-10
EP24305911 2024-06-10

Publications (1)

Publication Number Publication Date
WO2025257151A1 true WO2025257151A1 (fr) 2025-12-18

Family

ID=91700259

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/066063 Pending WO2025257151A1 (fr) 2024-06-10 2025-06-10 Méthodes et composition pharmaceutique pour le traitement de ciliopathies

Country Status (1)

Country Link
WO (1) WO2025257151A1 (fr)

Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
WO2006003388A2 (fr) 2004-06-30 2006-01-12 Domantis Limited Compositions et procedes pour le traitement de troubles inflammatoires
WO2006030220A1 (fr) 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
US20140068797A1 (en) 2012-05-25 2014-03-06 University Of Vienna Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
WO2014078309A1 (fr) 2012-11-13 2014-05-22 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Composés pour la médiation d'un récepteur des cannabinoïdes
WO2019211665A1 (fr) * 2018-04-30 2019-11-07 Takeda Pharmaceutical Company Limited Protéines de liaison du récepteur cannabinoïde de type 1 (cb1) et leurs utilisations
WO2021189141A1 (fr) 2020-03-24 2021-09-30 Inversago Pharma Inc. Dispersions solides de dérivés de 3,4-diphényl-4,5-dihydro-1h-pyrazole amorphes, compositions les comprenant et leurs utilisations en tant qu'inhibiteurs du récepteur cannabinoïde cb1

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression
WO2006003388A2 (fr) 2004-06-30 2006-01-12 Domantis Limited Compositions et procedes pour le traitement de troubles inflammatoires
WO2006030220A1 (fr) 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
US20140068797A1 (en) 2012-05-25 2014-03-06 University Of Vienna Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription
WO2014078309A1 (fr) 2012-11-13 2014-05-22 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Composés pour la médiation d'un récepteur des cannabinoïdes
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
WO2019211665A1 (fr) * 2018-04-30 2019-11-07 Takeda Pharmaceutical Company Limited Protéines de liaison du récepteur cannabinoïde de type 1 (cb1) et leurs utilisations
WO2021189141A1 (fr) 2020-03-24 2021-09-30 Inversago Pharma Inc. Dispersions solides de dérivés de 3,4-diphényl-4,5-dihydro-1h-pyrazole amorphes, compositions les comprenant et leurs utilisations en tant qu'inhibiteurs du récepteur cannabinoïde cb1

Non-Patent Citations (35)

* Cited by examiner, † Cited by third party
Title
"Genbank", Database accession no. NM _001160259
ATALA AFREEMAN MRMANDELL JBEIER DR: "Juvenile cystic kidneys (jck): a new mouse mutation which causes polycystic kidneys", KIDNEY INT, vol. 43, no. 5, May 1993 (1993-05-01), pages 1081 - 5
BAKEY ZBIHOREAU MTPIEDAGNEL RDELESTRÉ LARNOULD CDE VILLIERS A D'HOTMAN ET AL.: "The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes", KIDNEY INT, vol. 88, no. 2, August 2015 (2015-08-01), pages 299 - 310
DAO M, LECRU L, VANDERMEERSCH S, FERREIRA M, FERLICOT S, POSSEME K: "The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept", J CELL MOL MED, vol. 23, no. 11, November 2019 (2019-11-01), pages 7279 - 88
DAO MFRANGOIS H.: "Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox", FRONT ENDOCRINOL, vol. 12, 2021, pages 720734
DAO MYRIAM ET AL: "Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox", vol. 12, 7 July 2021 (2021-07-07), CH, XP093212421, ISSN: 1664-2392, Retrieved from the Internet <URL:https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.720734/full> [retrieved on 20241007], DOI: 10.3389/fendo.2021.720734 *
DEVLIN LAURA ET AL: "Renal ciliopathies: promising drug targets and prospects for clinical trials", EXPERT OPINION ON THERAPEUTIC TARGETS, vol. 27, no. 4-5, 4 May 2023 (2023-05-04), UK, pages 325 - 346, XP093212101, ISSN: 1472-8222, DOI: 10.1080/14728222.2023.2218616 *
DICARLO ET AL., NUCLEIC ACIDS RES., vol. 41, 2013, pages 4336 - 4343
FABRE ET AL., PLOS NEGL. TROP. DIS., vol. 8, 2014, pages 2671
FRANCOIS HJACQUET ABEAUDREUIL SSEIDOWSKY AHEBIBI HCHARPENTIER B ET AL.: "Emerging strategies to preserve renal function", J NEPHROL, vol. 24, no. 2, April 2011 (2011-04-01), pages 133 - 41
GRATZ ET AL., GENETICS, 2014
GUO ET AL., DEVELOPMENT, vol. 141, 2014, pages 707 - 714
HAI ET AL., CELL RES, 2014
HAI ET AL., CELL RES., vol. 24, 2014, pages 122 - 125
HEERSPINK HJLSTEFANSSON BVCORREA-ROTTER RCHERTOW GMGREENE THOU FF ET AL.: "Dapagliflozin in Patients with Chronic Kidney Disease", N ENGL J MED, vol. 383, no. 15, August 2020 (2020-08-01), pages 1436 - 46
HINDEN L, AHMAD M, HAMAD S, NEMIROVSKI A, SZANDA G, GLASMACHER S: "Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function", NAT COMMUN, vol. 13, no. 1, 4 April 2022 (2022-04-04), pages 1783
HOFF SHALBRITTER JEPTING DFRANK VNGUYEN TMTVAN REEUWIJK J ET AL.: "ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3", NAT GENET, vol. 45, no. 8, August 2013 (2013-08-01), pages 951 - 6
HWANG ET AL., PLOS ONE, vol. 8, 2013, pages 68708
JACQUOT LAETITIA ET AL: "Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy", vol. 3, 28 March 2023 (2023-03-28), XP093211939, ISSN: 2813-0626, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S016372582030005X> [retrieved on 20241004], DOI: 10.3389/fneph.2023.1138416 *
LECRU LDESTERKE CGRASSIN-DELYLE SCHATZIANTONIOU CVANDERMEERSCH SDEVOCELLE A ET AL.: "Cannabinoid receptor 1 is a major mediator of renal fibrosis", KIDNEY INT., vol. 88, no. 1, July 2015 (2015-07-01), pages 72 - 84, XP055676648, DOI: 10.1038/ki.2015.63
LOLA LECRU ET AL: "Cannabinoid receptor 1 is a major mediator of renal fibrosis", vol. 88, 1 January 2015 (2015-01-01), pages 72 - 84, XP055676648, Retrieved from the Internet <URL:https://pubmed.ncbi.nlm.nih.gov/25760323/> [retrieved on 20241004], DOI: 10.1038/ki.2015.63 *
MALI ET AL., SCIENCE, vol. 339, 2013, pages 823 - 826
MARTIN-BELMONTE FGASSAMA ADATTA AYU WRESCHER UGERKE V ET AL.: "PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42", CELL, vol. 128, no. 2, 26 January 2007 (2007-01-26), pages 383 - 97
MASHIKO ET AL., DEV. GROWTH DIFFER., vol. 56, 2014, pages 122 - 129
MASYUKOVA SVLANDIS DEHENKE SJWILLIAMS CLPIECZYNSKI JNROSZCZYNIALSKI KN ET AL.: "A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4", PLOS GENET, vol. 12, no. 2, February 2016 (2016-02-01), pages 1005841
MCCONNACHIE DJSTOW JLMALLETT AJ.: "Ciliopathies and the Kidney: A Review", AM J KIDNEY DIS OFF J NATL KIDNEY FOUND, vol. 77, no. 3, 2021, pages 410 - 9
MIILLER RU, MESSCHENDORP AL, BIRN H, CAPASSO G, CORNEC-LE GALL E, DEVUYST O: "An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International", NEPHROL DIAL TRANSPLANT OFF PUBL EUR DIAL TRANSPL ASSOC - EUR REN ASSOC, vol. 37, no. 5, 2022, pages 825 - 39
NIU ET AL., CELL, vol. 156, 2014, pages 836 - 843
SCHWARZ HPOPP BAIRIK RTORABI NKNAUP KXSTOECKERT J ET AL.: "Biallelic ANKS6 mutations cause late-onset ciliopathy with chronic kidney disease through YAP dysregulation", HUM MOL GENET, vol. 31, no. 9, 4 May 2022 (2022-05-04), pages 1357 - 69
SHERPA RT, ATKINSON KF, FERREIRA VP, NAULI SM.: "RAPAMYCIN INCREASES LENGTH AND MECHANOSENSORY FUNCTION OF PRIMARY CILIA IN RENAL EPITHELIAL AND VASCULAR ENDOTHELIAL CELLS ", INT EDUC RES J, vol. 2, no. 12, December 2016 (2016-12-01), pages 91 - 7
SMITH LABUKANOV NOHUSSON HRUSSO RJBARRY TCTAYLOR AL ET AL.: "Development of Polycystic Kidney Disease in Juvenile Cystic Kidney Mice: Insights into Pathogenesis, Ciliary Abnormalities, and Common Features with Human Disease", J AM SOC NEPHROL, vol. 17, no. 10, October 2006 (2006-10-01), pages 2821 - 31
SULLIVAN LPWALLACE DPGRANTHAM JJ.: "Epithelial transport in polycystic kidney disease", PHYSIOL REV, vol. 78, no. 4, October 1998 (1998-10-01), pages 1165 - 91
TSUKAMOTO SURATE SYAMADA TAZUSHIMA KYAMAJI TKINGUCHI S ET AL.: "Comparative Efficacy of Pharmacological Treatments for Adults With Autosomal Dominant Polycystic Kidney Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials", FRONT PHARMACOL, vol. 13, 2022, pages 885457
YANG ET AL., J. MOL. CELL BIOL., vol. 6, 2014, pages 97 - 99
ZETSCHE ET AL.: "Cpf1 is a Single RNA-guided Endonuclease of a Class 2 CRISPR-Cas System", CELL, vol. 163, 2015, pages 1 - 13

Similar Documents

Publication Publication Date Title
JP6579629B2 (ja) 筋障害を相殺するための手段と方法
JP2024020338A (ja) 白斑を処置するための方法及び組成物
Vallières Trabedersen, a TGFbeta2-specific antisense oligonucleotide for the treatment of malignant gliomas and other tumors overexpressing TGFbeta2
KR20260005402A (ko) 암 치료를 위한 조성물 및 방법
US10059946B2 (en) Method for treatment of heart failure
WO2025257151A1 (fr) Méthodes et composition pharmaceutique pour le traitement de ciliopathies
US20220249511A1 (en) Methods for the treatment of keloid, hypertrophic scars and/or hyperpigmentation disorders
EP4088742A2 (fr) Composition pour prévenir ou traiter la dégénérescence maculaire, contenant un complexe d&#39;acide nucléique pouvant pénétrer dans les cellules en tant que principe actif
AU2024289222A1 (en) Il-1ra blockers for treatment and prevention of sepsis
JP2023548597A (ja) がんを処置するための可溶性インターロイキン－７受容体（ｓＩＬ７Ｒ）変調療法
US20210275543A1 (en) Methods for the treatment of mitochondrial genetic diseases
WO2026057679A1 (fr) Inhibiteur de rab30 destiné à être utilisé dans une méthode de traitement d&#39;une stéatose hépatique associée à un dysfonctionnement métabolique (masld)
US11066671B2 (en) Use of therapeutic agents
WO2025132479A1 (fr) Inhibiteur de flt3 pour moduler la polarisation de macrophages
Yang et al. Blockade of TLR2 activation in macrophages by self-assembled hyaluronic acid nanoparticles alleviates psoriasis-like skin dermatitis
WO2025248102A1 (fr) Inhibiteur de tbk1 destiné à être utilisé dans le traitement du vitiligo
WO2018178029A1 (fr) Méthodes et compositions pour le traitement d&#39;états ou de maladies musculaires et/ou neurologiques dégénératifs
HK1186377B (en) Means and methods for counteracting muscle disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25731297

Country of ref document: EP

Kind code of ref document: A1