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WO-2026093616-A1 - NUCLEIC ACID ENCODING CONE-ROD HOMEOBOX (CRX) PROTEIN, AND EXPRESSION VECTORS THEREOF, FOR USE IN TREATING A CILIOPATHY

WO2026093616A1WO 2026093616 A1WO2026093616 A1WO 2026093616A1WO-2026093616-A1

Abstract

The present invention relates to nucleic acids, expression vectors, and pharmaceutical compositions useful for treating a ciliopathy. The present invention also relates to methods for treating a ciliopathy in a subject in need thereof.

Inventors

  • ROGER, Jérôme
  • ROZET, JEAN-MICHEL

Assignees

  • VARIANT
  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
  • RETINA FRANCE
  • UNIVERSITE PARIS SACLAY
  • FONDATION IMAGINE
  • UNIVERSITE PARIS CITE
  • ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS
  • INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Dates

Publication Date
20260507
Application Date
20251104
Priority Date
20241104

Claims (15)

  1. 1. A nucleic acid comprising a sequence encoding a cone-rod homeobox (CRX) protein or a functional variant thereof, for use in a method for treating a retinopathy associated to a ciliopathy in a subject in need thereof.
  2. 2. An expression vector for use in a method for treating a retinopathy associated to a ciliopathy in a subject in need thereof; the expression vector comprising a nucleic acid comprising a sequence encoding a cone-rod homeobox (CRX) protein or a functional variant thereof.
  3. 3. The expression vector for use according to claim 2, wherein the expression vector is a recombinant adeno-associated virus (rAAV) vector.
  4. 4. The expression vector for use according to claim 3, wherein the rAAV vector is a pseudotyped rAAV vector.
  5. 5. The expression vector for use according to claim 3 or claim 4, wherein the rAAV vector comprises an AAV capsid protein from an AAV serotype selected from the group consisting of: AAV2, AAV5 and AAV8.
  6. 6. A nanoparticle for use in a method for treating a retinopathy associated to a ciliopathy in a subject in need thereof; the nanoparticle comprising a nucleic acid comprising a sequence encoding a cone-rod homeobox (CRX) protein or a functional variant thereof.
  7. 7. A pharmaceutical composition for use in a method for treating a retinopathy associated to a ciliopathy in a subject in need thereof; characterized in that it comprises (i) at least one of a nucleic acid according to claim 1, and/or at least one expression vector according to any of claims 2 to 5, and/or at least one nanoparticle according to claim 6, and (ii) a pharmaceutically acceptable excipient.
  8. 8. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 7; wherein the sequence encoding the CRX protein is operably liked to a promoter allowing the expression in a cone and/or rod photoreceptors.
  9. 9. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 8; which is administrable via a route selected from the group consisting of: oral, sublingual, buccal, rectal, intravenous, intramuscular, subcutaneous, intranasal, inhalational, vaginal, transdermal, intravitreal, subretinal and suprachoroidal; preferably intravitreal, subretinal and suprachoroidal.
  10. 10. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 9; which is administrable in a dose ranging from 10 8 copies per dose to 10 14 copies per dose; more preferably ranging from 10 9 to 3.10 12 copies per dose.
  11. 11. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 10; wherein the retinopathy associated to a ciliopathy is selected from the group consisting of: Retinal dystrophy (RD) associated to a ciliopathy, Retinitis pigmentosa (RP) associated to a ciliopathy, Leber Congenital Amaurosis (LCA) associated to a ciliopathy, Cone-Rod Dystrophy (CRD) associated to a ciliopathy, Nephronopthisis (NPHP) associated to a ciliopathy, Senior Loken syndrome (SLSN) associated to a ciliopathy, Joubert Syndrome (JBTS) associated to a ciliopathy, Meckel Gruber syndrome (MKS) associated to a ciliopathy, Bardet- Biedl syndrome (BBS) associated to a ciliopathy, Short-rib thoracic dysplasia (SRTD) associated to a ciliopathy, Usher Syndrome associated to a ciliopathy, Alstrdm Syndrome associated to a ciliopathy and Orafaciodigital Syndrome associated to a ciliopathy.
  12. 12. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 11; wherein the retinopathy associated to a ciliopathy is associated to one or more mutation in one or more gene of Centrosomal Protein (CEP), preferably on one or more genes selected from the group consisting of: CEP290, CEP 164, CEP 162, CEP120, CEP104, CEP55 and. CEP41; and even more preferably CEP290.
  13. 13. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 11; wherein the retinopathy associated to a ciliopathy is associated to one or more mutation in one or more gene of Nephronophthisis (NPHP), preferably on one or more genes selected from the group consisting of: NPHP1, NPHP2, NPHP3, NPHP4, NPHP 5, NPHP6, NPHP7, NPHP8, NPHP9, NPHP 10, NPHP11, NPHP12, NPHP13, NPHP14, NPHP 15, NPHP16, NPHP 17, NPHP 18, NPHP19 and NPHP20; preferably NPHP1 and NPHP6.
  14. 14. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 13; wherein the subject in need thereof is not associated to a mutation in gene CRX.
  15. 15. The nucleic acid for use, the expression vector for use, the nanoparticle for use, or the pharmaceutical composition for use according to any one claims 1 to 14; wherein the subject is a mammalian subject, preferably a human subject.

Description

NUCLEIC ACID ENCODING CONE-ROD HOMEOBOX (CRX) PROTEIN, AND EXPRESSION VECTORS THEREOF, FOR USE IN TREATING A CILIOPATHY FIELD OF INVENTION [0001] The present invention relates to gene therapy. [0002] The present invention relates to nucleic acids, expression vectors, and pharmaceutical compositions useful for treating a ciliopathy. The present invention also relates to methods for treating a ciliopathy in a subject in need thereof. [0003] In particular the present invention relates to a gene therapy applicable to the treatment of a ciliopathy; more particularly a CEP290INPHP 1 -related ciliopathy and/or a ciliopathy causing retinal degeneration. The present invention relates especially to a gene therapy applicable to the treatment of retinal ciliopathies, whether non syndromic or syndromic, and more particularly to those associated with CEP290 or NPHP1 mutations BACKGROUND OF INVENTION [0004] Ciliopathies are genetic disorders that affect the cellular cilia and/or the cilia anchoring structures, the basal bodies and/or the ciliary function. Such genetic disorders are associated with a wide variety of symptoms, which may affect a number of organs, including (in a non-limitative manner) those associated with visual impairment. This cilium may include the photoreceptor transition zone, known as the photoreceptor connecting cilium, and/or axonemal extension known as the outer segment. [0005] In fact, the diagnosis of ciliopathies is based on a multidisciplinary approach, which may combine clinical criteria, genetic analyses, and additional investigations. This can include functional assessments of cilia, ophthalmological examinations, and genetic testing. [0006] Among the ciliary genes involved in ciliopathies, CEP290 is a protein encoded by a gene (i.e., CEP290 in human and Cep290 in mice) that plays a crucial role in the development and function of cilia. In fact, disrupted Cep290 mouse is well known model representative of ciliopathy for skilled person. Mutations in this gene can lead to a wide range of disorders, collectively known as ciliopathies; such as Leber Congenital Amaurosis, Retinitis Pigmentosa, Cone-Rod Dystrophy, Senior-Loken Syndrome, Joubert Syndrome, Nephronophthisis, Meckel-Gruber Syndrome, Bardet-Biedl syndrome. These conditions also affect various organs and systems in the body. [0007] Such ciliopathies may include, in particular, retinal ciliopathies, such as syndromic retinal disorders and non- syndromic retinal disorders. Retinal ciliopathies represent a subgroup of inherited retinal diseases (IRDs), which can be characterized by structural or functional abnormalities of the photoreceptor cilia. [0008] In particular, inherited retinal diseases (IRDs) are common causes of visual impairment. They form a group of genetically and clinically heterogeneous diseases. IRDs are characterized by photoreceptor cell death and form a group of clinically and genetically heterogeneous diseases with more than 300 genes identified. For example, IRDs are frequently associated with ciliopathies due to the crucial role of ciliary function in maintaining the integrity of photoreceptor cells. Disruptions in this function can lead to progressive degeneration of the retina and subsequent vision impairment. [0009] Approximatively 25% of the gene defects underlying retinal degeneration affect the structure or function of the ‘connecting cilium’ in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating the bi-directional transport of all proteins required for vision transduction and therefore vision. The outer segment, connecting the cilium and associated basal body, forms a highly specialised sensory cilium dedicated to photoreception and subsequent signal transduction, where the light is converted into a neuro-electrophysiological signal, processed throughout the retina, and transmitted to the brain via the optic nerve. [0010] Attempts to treat ciliopathies, or to attenuate their progression have been reported in the past. See, for example, Paff et al. (“Current and Future Treatments in Primary Ciliary Dyskinesia”; International Journal of Molecular Sciences; 2021, 22, 9834). [0011] Reference is further made to WO2020/182722 which reports a recombinant AAV vector carrying a nucleic acid sequence encoding the retinal transcription factor cone-rod homeobox (CRX) for use in treating a CRX-associated Inherited retinal diseases (IRD). [0012] Yet, there remains a need for means for treating ciliopathies, and for treating or preventing and/or reducing the likelihood of occurrence, or the likelihood of reoccurrence, of symptoms thereof. [0013] In particular, there remains a need for treating ocular ciliopathies, and for treating or preventing and/or reducing the likelihood of occurrence, or the likelihood of reoccurrence of ciliopa