Correction of human nonsense mutation via adenine base editing for Duchenne muscular dystrophy treatment in mouse.

Autor:	Jin M; Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350004, China., Lin J; Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350004, China., Li H; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China.; School of Medicine, Wayne State University, Detroit, MI 48201, USA., Li Z; Lingang Laboratory, Shanghai 200031, China., Yang D; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China., Wang Y; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China., Yu Y; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China., Shao Z; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China., Chen L; Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350004, China., Wang Z; Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350004, China., Zhang Y; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China., Zhang X; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China., Wang N; Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350004, China., Xu C; Lingang Laboratory, Shanghai 200031, China.; Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai 201602, China., Yang H; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China.; Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.; Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai 201602, China., Chen WJ; Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou 350004, China., Li G; HuidaGene Therapeutics Co., Ltd, Shanghai 200131, China.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Mar 06; Vol. 35 (2), pp. 102165. Date of Electronic Publication: 2024 Mar 06 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102165
Abstrakt:	Duchenne muscular dystrophy (DMD) is the most prevalent herediatry disease in men, characterized by dystrophin deficiency, progressive muscle wasting, cardiac insufficiency, and premature mortality, with no effective therapeutic options. Here, we investigated whether adenine base editing can correct pathological nonsense point mutations leading to premature stop codons in the dystrophin gene. We identified 27 causative nonsense mutations in our DMD patient cohort. Treatment with adenine base editor (ABE) could restore dystrophin expression by direct A-to-G editing of pathological nonsense mutations in cardiomyocytes generated from DMD patient-derived induced pluripotent stem cells. We also generated two humanized mouse models of DMD expressing mutation-bearing exons 23 or 30 of human dystrophin gene. Intramuscular administration of ABE, driven by ubiquitous or muscle-specific promoters could correct these nonsense mutations in vivo , albeit with higher efficiency in exon 30, restoring dystrophin expression in skeletal fibers of humanized DMD mice. Moreover, a single systemic delivery of ABE with human single guide RNA (sgRNA) could induce body-wide dystrophin expression and improve muscle function in rotarod tests of humanized DMD mice. These findings demonstrate that ABE with human sgRNAs can confer therapeutic alleviation of DMD in mice, providing a basis for development of adenine base editing therapies in monogenic diseases. Competing Interests: H.Y. is a founder of HuidaGene Therapeutics. (© 2024 The Author(s).)
Databáze:	MEDLINE
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