Liver-Directed Gene Therapy Shows Durable Effect in MMA Mouse Model

Genespire, in collaboration with the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), reported findings published in the Journal of Hepatology showing that liver-directed delivery of an immune-shielded lentiviral vector (ISLV) encoding the MMUT gene produced durable therapeutic benefits in a validated mouse model of methylmalonic acidemia (MMA).^1,2 Systemic administration to 2-week-old MMA mice produced a rapid and long-lasting effect, sustained for more than a year, or roughly the average laboratory mouse lifespan, with normalization of liver histology and mitochondrial ultrastructure.²

MMA is a rare inherited metabolic disorder caused by deficiency of methylmalonyl-CoA mutase, the enzyme encoded by MMUT. Loss of enzyme function leads to accumulation of toxic metabolites, recurrent metabolic crises, growth failure, neurological impairment, and multi-organ damage; no disease-targeted therapies are currently approved.¹

An optimized version of the MMUT transgene produced dose-dependent improvement in metabolic biomarkers and hepatocyte transduction efficiency exceeding 80% in the same model.^1,2 At lower doses, corrected hepatocytes showed a selective proliferative advantage over diseased cells, suggesting therapeutic efficacy could improve over time even from a lower starting dose.¹ Vector integration site analysis showed a high number of integrations without dominant clones, consistent with a polyclonal profile.² The therapy also produced metabolic improvement in adult MMA mice with more advanced disease, and restored MMUT expression in patient-derived fibroblasts in vitro.²

"Together, these findings indicate that Genespire is on a clear path towards the long-term correction of metabolic diseases which impact the liver and other organs," Lucia Faccio, CEO of Genespire, said in a statement.¹ The company is advancing its lead MMA program, GENE202, toward clinical development.

"We are confident that this study, together with other previous studies from our group at SR-TIGET, provides a comprehensive preclinical data package enabling the initiation of clinical testing in pediatric patients affected by MMA," said Alessio Cantore, PhD, group leader at SR-TIGET and associate professor at Vita-Salute San Raffaele University, who supervised the study and served as senior author.¹

The data remain limited to animal models and in vitro fibroblast work; no clinical trial in humans has yet been initiated.

REFERENCES
1. Genespire and SR-TIGET show durable preclinical efficacy of liver-directed gene therapy for methylmalonic acidemia. News release. Genespire. July 8, 2026. Accessed July 21, 2026. https://www.prnewswire.com/news-releases/genespire-and-sr-tiget-show-durable-preclinical-efficacy-of-liver-directed-gene-therapy-for-methylmalonic-acidemia-302819929.html
2. Manta E, Biffi M, Sanvito F, et al. Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice. J Hepatol. 2026. doi:10.1016/j.jhep.2026.05.011. https://www.sciencedirect.com/science/article/pii/S0168827826002886