Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice - PubMed
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- #methylmalonic acidemia
- #lentiviral gene therapy
- #liver-directed therapy
- Liver-directed lentiviral gene therapy in a mouse model of methylmalonic acidemia (MMA) led to long-lasting (>1 year) therapeutic effects, including normalized liver histology and mitochondrial ultrastructure.
- Treatment resulted in systemic detoxification and broad correction of metabolomic, lipidomic, and proteomic profiles, with supraphysiological hepatic MMUT expression providing extrahepatic benefits.
- A codon-optimized MMUT transgene improved expression, allowed lower therapeutic doses, and conferred a selective proliferative advantage to corrected hepatocytes, achieving high transduction efficiency (>80%).
- LV integration analysis showed a polyclonal profile without dominant clones, and therapy was effective even in adult mice with advanced disease, supporting safety and efficacy.
- In vitro, LV restored MMUT expression in patient-derived fibroblasts, partially correcting metabolic abnormalities, offering preclinical proof-of-concept for clinical translation.