公开(公告)号：US20230136699A1

公开(公告)日：2023-05-04

申请号：US17904124

申请日：2021-02-26

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

发明人： Manuel SCHIFF ,  Marina CAVAZZANA ,  Pascale DE LONLAY-DEBENEY ,  Marcelo SIMON SOLA ,  Clément PONTOIZEAU ,  Chris OTTOLENGHI

IPC分类号： C12N9/02 ,  C12N15/86 ,  A61P3/00 ,  A61P13/00 ,  A61K38/44

摘要： Maple syrup urine disease (MSUD) is a rare autosomal recessive disease with an incidence that is caused by a defective activity of the branched-chain 2-keto acid dehydrogenase (BCKD) leading to accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine and their corresponding alpha-ketoacids (BCKA) in tissues and body fluids. The inventors herein characterized the Bckdha−/− mouse and Bckdhb−/− mouse recapitulating the classical forms of MSUD. As a proof of concept, they developed a (liver-directed) AAV gene therapy based on the transfer of human BCKDHA (hBCKDHA) or BCKDHB (hBCKDHB) mediated by AAV8 during immediate neonatal period in Bckdha−/− or Bckdhb−/− mice. The inventors demonstrated that hBCKDHA gene transfer completely rescued the lethal early-onset phenotype of Bckdha−/− mice allowing long-term survival to age 12 months, at which they were systematically sacrificed, without overt phenotypic abnormalities. They also demonstrated that hBCKDHB gene transfer exhibited similar survival and a normal growth without overt phenotypic abnormalities at age 3 months, with a dramatic improvement of the biochemical phenotype. The present invention relates to a method of treating MSUD by gene therapy.

公开(公告)号：US20240238235A1

公开(公告)日：2024-07-18

申请号：US18561797

申请日：2022-05-25

申请人： INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE ,  UNIVERSITE PARIS CITE ,  CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) ,  FONDATION IMAGINE ,  ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP)

发明人： Alice HADCHOUEL-DUVERGE ,  Manuel SCHIFF ,  Clément PONTOIZEAU

IPC分类号： A61K31/198 ,  A61K9/00 ,  A61P11/00 ,  G01N33/68

CPC分类号： A61K31/198 ,  A61K9/0053 ,  A61P11/00 ,  G01N33/6884 ,  G01N2800/12

摘要： The present invention relates to a method for treating pulmonary alveolar proteinosis related to MARS gene mutations in a subject in need thereof comprising a step of administering said subject with a therapeutically effective amount of supplementation of methionine and/or its derivatives. Pulmonary alveolar proteinosis related to mutations in the gene encoding the methionine tRNA synthetase is a severe, early-onset lung disease that also associates liver involvement, failure to thrive, and systemic inflammation. Inventors describe an infant affected by this disease who was successfully treated by oral methionine supplementation. After three months of treatment she was free of respiratory symptoms, inflammation and cholestasis resolved, and there was a catchup in growth. Her bronchoalveolar lavage fluid was free of extracellular lipoproteinaceous material. Functional assays on peripheral monocytes, initially altered, normalized. This study paves the way for similar strategies in other tRNA synthetase deficiencies.