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    METHODS FOR THE TREATMENT OF RETINAL DYSTROPHIES BY EXON-SKIPPING STRATEGY
    1.
    发明申请
    METHODS FOR THE TREATMENT OF RETINAL DYSTROPHIES BY EXON-SKIPPING STRATEGY 有权

    公开(公告)号：US20220340901A1

    公开(公告)日：2022-10-27

    申请号：US17606574

    申请日：2020-04-24

    申请人： INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) ,  FONDATION ASILE DES AVEUGLES ,  UNIVERSITÉ DE PARIS ,  ASSISTANCE PUBLIQUE - HÔPITAUX DE PARIS ,  FONDATION IMAGINE

    发明人： Jean-Michel Rozet ,  Xavier GERARD ,  Iris BARNY ,  Isabelle PERRAULT ,  Josseline KAPLAN

    IPC分类号： C12N15/113

    摘要： The invention relates to the skipping of the CEP290 exon 36 in an individual suffering from a retinal dystrophy accounted for by a nonsense mutation or a premature termination codon generated by a frameshift mutation in exon 36 or an upstream exon, including the c.4723A>T, c.4771C>T, c.4714G>T, c.4786_4790del, c.4791_4794del, c.4732G>T, c.4625_4626insCATG (35), c.4792_4795del, c.4801C>T, c.4805C>T, or c.4811G>A mutations, to bypass protein truncation and lessen retinal damages. Here, studying fibroblasts from control individuals, and two patients carrying the CEP290 c.4723A>T nonsense mutation, they show low levels of spontaneous skipping of exon 36 arising from both endogenous basal skipping and mutation-induced skipping. The minimally shortened and mutation-free CEP290 mRNA produced by skipping of exon 36 in the fibroblasts of the two patients is translated into a protein isoform that localizes at the centrosome and allows the formation of primary cilia, yet with elongated axonemes. Using an AON consisting of a sequence set forth as SEQ ID NO: 1, complementary to a nucleic acid sequence of CEP290 pre-mRNA, wherein said AON targeting an mRNA encoding the donor splice site (H36D) is capable to alter splicing by blocking the recognition of exon 36 and bypass protein truncation while maintaining the open reading frame, leading to the production of near full-length CEP290 protein, they were able to increase the abundance of the alternatively spliced mRNA and shortened protein and to reduce axonemal length in patient cells.