Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.

Autor: Morelli KH; The Jackson Laboratory, Bar Harbor, Maine, USA.; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA., Griffin LB; Program in Cellular and Molecular Biology, and.; Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA., Pyne NK; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Wallace LM; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Fowler AM; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA., Oprescu SN; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA., Takase R; Department of Biochemistry and Molecular Biochemistry, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Wei N; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Meyer-Schuman R; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA., Mellacheruvu D; Department of Pathology, and.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA., Kitzman JO; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA., Kocen SG; The Jackson Laboratory, Bar Harbor, Maine, USA., Hines TJ; The Jackson Laboratory, Bar Harbor, Maine, USA., Spaulding EL; The Jackson Laboratory, Bar Harbor, Maine, USA.; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA., Lupski JR; Department of Molecular and Human Genetics, and.; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Nesvizhskii A; Department of Pathology, and.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA., Mancias P; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, and Children's Memorial Hermann Hospital, Houston, Texas, USA., Butler IJ; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, and Children's Memorial Hermann Hospital, Houston, Texas, USA., Yang XL; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Hou YM; Department of Biochemistry and Molecular Biochemistry, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Antonellis A; Program in Cellular and Molecular Biology, and.; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA., Harper SQ; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA., Burgess RW; The Jackson Laboratory, Bar Harbor, Maine, USA.; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2019 Dec 02; Vol. 129 (12), pp. 5568-5583.
DOI: 10.1172/JCI130600
Abstrakt: Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.
Databáze: MEDLINE