Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.

Autor:	Zhang S; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Bastille A; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Gordo S; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Ramesh N; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Vora J; LogicBio Therapeutics Inc., Lexington, MA, United States of America., McCarthy E; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Zhang X; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Frank D; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Ko CW; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Wu C; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Walsh N; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Amarwani S; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Liao J; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Xiong Q; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Drouin L; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Hebben M; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Chiang K; LogicBio Therapeutics Inc., Lexington, MA, United States of America., Chau BN; LogicBio Therapeutics Inc., Lexington, MA, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2022 Sep 20; Vol. 17 (9), pp. e0274774. Date of Electronic Publication: 2022 Sep 20 (Print Publication: 2022).
DOI:	10.1371/journal.pone.0274774
Abstrakt:	Methylmalonic acidemia (MMA) is an inborn error of metabolism mostly caused by mutations in the mitochondrial methylmalonyl-CoA mutase gene (MMUT). MMA patients suffer from frequent episodes of metabolic decompensation, which can be life threatening. To mimic both the dietary restrictions and metabolic decompensation seen in MMA patients, we developed a novel protein-controlled diet regimen in a Mmut deficient mouse model of MMA and demonstrated the therapeutic benefit of mLB-001, a nuclease-free, promoterless recombinant AAV GeneRideTM vector designed to insert the mouse Mmut into the endogenous albumin locus via homologous recombination. A single intravenous administration of mLB-001 to neonatal or adult MMA mice prevented body weight loss and mortality when challenged with a high protein diet. The edited hepatocytes expressed functional MMUT protein and expanded over time in the Mmut deficient mice, suggesting a selective growth advantage over the diseased cells. In mice with a humanized liver, treatment with a human homolog of mLB-001 resulted in site-specific genome editing and transgene expression in the transplanted human hepatocytes. Taken together, these findings support the development of hLB-001 that is currently in clinical trials in pediatric patients with severe forms of MMA. Competing Interests: The authors are/were employees of LogicBio Therapeutics. LogicBio has filed pending patent applications published as WO2020/032986 (pertaining to non-disruptive gene therapy for the treatment of MMA) and WO2020/214582 (pertaining to monitoring gene therapy). This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze:	MEDLINE
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