bioRxiv : the preprint server for biologyApr 10, 2026

Fixing a common genetic mutation causing methylmalonic acidemia using precise DNA base editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Adenine base editing may correct the recurrent MMAB c.556C>T (R186W) methylmalonic acidemia variant in hepatocytes.

Evidence

This was an in vitro gene-editing platform experiment using adenine base editor mRNA, optimized hybrid guide RNA, and lipid nanoparticles to edit hepatocytes.

Caveat

The abstract reports hepatocyte editing rather than animal or patient outcomes, so therapeutic delivery, durability, safety, and clinical benefit remain untested.

Simplified

Methylmalonic acidemia (MMA) is a recessive genetic disease caused by variants in the(mitochondrial enzyme methylmalonyl-CoA mutase) gene or by defects in transport or metabolism of MMUT cofactor (5' deoxyadenosylcobalamin), including variants in thegene. For the most recurrent pathogenicvariant, c.556C>T (R186W), we identified a corrective editing strategy using adenine base editing. Deploying an adenine base editor mRNA and optimized hybrid guide RNA with lipid nanoparticles, we observed efficientcorrective editing of the variant to wild-type, with minimized bystander editing and off-target editing in hepatocytes. These observations lay the groundwork for a gene editing therapy for patients with MMA resulting from at least one copy of thec.556C>T (R186W) variant, as well as a platform of similar therapies for patients with MMA caused by other variants amenable to adenine base editing. MMUT MMAB MMAB in vitro MMAB

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Fixing a common genetic mutation causing methylmalonic acidemia using precise DNA base editing

Abstract

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