Journal of hepatology · 2026
Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice.
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Barbon Elena, Simoni Chiara, Argabright Amy, Boettiger Molly, Negri Camilla, Manta Elisabetta, Raimondi Andrea, Vezzoli Elena, Canepari Cesare, Biffi Mauro, Nonis Alessandro, Gazzo Francesco, Benedicenti Fabrizio, Montini Eugenio, la Marca Giancarlo, Sanvito Francesca, Smith Julianne, D'Alessandro Angelo, Cantore Alessio
Аннотация
BACKGROUND & AIMS: Isolated methylmalonic acidemia (MMA) is a severe inherited metabolic disorder caused by a deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase, encoded by the MMUT gene. Lentiviral vector (LV)-based liver gene therapy may offer sustained therapeutic benefits even in paediatric patients, whose livers are still growing, due to the stable genomic integration of the therapeutic transgene.
METHODS: We evaluated the efficacy of liver-directed LV gene therapy in a mouse model of MMA and in patient-derived human fibroblasts.
RESULTS: Systemic administration of an MMUT-expressing LV to 2-week-old MMA mice yielded a rapid, strong, and long-lasting (>1 year) therapeutic effect, with normalization of liver histology and mitochondrial ultrastructure. LV-mediated supraphysiological hepatic expression of MMUT promoted detoxification of the kidney and brain from methylmalonic acid and achieved broad correction of metabolomic, lipidomic, and proteomic profiles. Subsequently, we developed a codon-optimized MMUT transgene to increase expression and lower the minimal therapeutic dose. In 2-week-old MMA mice, this LV variant showed a dose-dependent improvement in metabolic biomarkers, clinical phenotype, and hepatocyte transduction efficiency (exceeding 80%). At the lower LV doses, corrected hepatocytes showed a selective proliferative advantage. Throughout all treated animals, LV integration site analysis revealed a high number of integrations without dominant clones, supporting a polyclonal profile. LV gene therapy provided metabolic improvement even in adult MMA mice, which had a more advanced disease stage than 2-week-old MMA mice. In vitro, LV delivery restored MMUT expression in patient-derived fibroblasts and partially corrected their metabolic abnormalities.
CONCLUSION: These data provide preclinical proof-of-concept for the efficacy, safety, and extrahepatic therapeutic benefit of liver-directed LV gene therapy for MMA.
IMPACT AND IMPLICATIONS: Methylmalonic acidemia (MMA) is a severe metabolic disorder with few treatment options. A liver-targeted gene therapy using integrating lentiviral vectors (LV) could allow for treatment of pediatric patients with a single dose, due to the stable integration of the therapeutic transgene into the DNA of target cells. In this study, we showed that in a relevant MMA mouse model, systemic LV administration led to long-lasting expression of the therapeutic enzyme in hepatocytes, which corrected metabolic abnormalities and significantly improved the disease phenotype. Supranormal enzyme levels in the liver enabled systemic detoxification and widespread metabolic normalization without detectable LV-related toxicity. We provide a detailed LV dose-response study evaluating the efficiency of gene transfer to hepatocytes and its therapeutic outcomes. Overall, these findings offer strong preclinical evidence to support progressing to clinical trials for patients with MMA and may help guide the use of liver-directed LV gene therapy for other inherited metabolic diseases.
METHODS: We evaluated the efficacy of liver-directed LV gene therapy in a mouse model of MMA and in patient-derived human fibroblasts.
RESULTS: Systemic administration of an MMUT-expressing LV to 2-week-old MMA mice yielded a rapid, strong, and long-lasting (>1 year) therapeutic effect, with normalization of liver histology and mitochondrial ultrastructure. LV-mediated supraphysiological hepatic expression of MMUT promoted detoxification of the kidney and brain from methylmalonic acid and achieved broad correction of metabolomic, lipidomic, and proteomic profiles. Subsequently, we developed a codon-optimized MMUT transgene to increase expression and lower the minimal therapeutic dose. In 2-week-old MMA mice, this LV variant showed a dose-dependent improvement in metabolic biomarkers, clinical phenotype, and hepatocyte transduction efficiency (exceeding 80%). At the lower LV doses, corrected hepatocytes showed a selective proliferative advantage. Throughout all treated animals, LV integration site analysis revealed a high number of integrations without dominant clones, supporting a polyclonal profile. LV gene therapy provided metabolic improvement even in adult MMA mice, which had a more advanced disease stage than 2-week-old MMA mice. In vitro, LV delivery restored MMUT expression in patient-derived fibroblasts and partially corrected their metabolic abnormalities.
CONCLUSION: These data provide preclinical proof-of-concept for the efficacy, safety, and extrahepatic therapeutic benefit of liver-directed LV gene therapy for MMA.
IMPACT AND IMPLICATIONS: Methylmalonic acidemia (MMA) is a severe metabolic disorder with few treatment options. A liver-targeted gene therapy using integrating lentiviral vectors (LV) could allow for treatment of pediatric patients with a single dose, due to the stable integration of the therapeutic transgene into the DNA of target cells. In this study, we showed that in a relevant MMA mouse model, systemic LV administration led to long-lasting expression of the therapeutic enzyme in hepatocytes, which corrected metabolic abnormalities and significantly improved the disease phenotype. Supranormal enzyme levels in the liver enabled systemic detoxification and widespread metabolic normalization without detectable LV-related toxicity. We provide a detailed LV dose-response study evaluating the efficiency of gene transfer to hepatocytes and its therapeutic outcomes. Overall, these findings offer strong preclinical evidence to support progressing to clinical trials for patients with MMA and may help guide the use of liver-directed LV gene therapy for other inherited metabolic diseases.