Genespire, in collaboration with the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), has published preclinical data demonstrating the durability and efficacy of its liver-directed immune-shielded lentiviral gene therapy for methylmalonic acidemia (MMA), a severe inherited metabolic disorder. The study, published in the Journal of Hepatology, shows that a single systemic administration of a lentiviral vector encoding the MMUT gene led to sustained improvements in disease features in a validated mouse model of MMA, with effects lasting for the average lifespan of laboratory mice.
High Gene Transfer Efficiency and Therapeutic Benefits
The research highlights that gene transfer efficiency exceeded 80% of the liver, leading to dose-dependent improvement of metabolomic biomarkers. In the study, researchers treated mice with an optimized MMUT transgene, which enhanced therapeutic efficacy. The findings indicate that genetically corrected cells in the liver may replace diseased cells over time, suggesting that therapeutic efficacy could progressively improve even at lower initial doses.
Potential for Single-Administration Treatment
MMA is caused by a deficiency of methylmalonyl-CoA mutase, an enzyme critical for metabolizing food. Its absence leads to toxic metabolite accumulation, causing recurrent metabolic crises, growth failure, neurological impairment, and multi-organ damage. According to Lucia Faccio, CEO of Genespire, “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. We believe our approach has the potential to translate into human health in the form of a single-administration treatment for patients with MMA, and are committed to continuing our efforts in bringing our lead asset for MMA, GENE202, to the clinic.”
Next Steps Toward Clinical Testing
The study also treated mice when young, supporting the durability of the gene therapy through postnatal growth and maturation of the liver. Dr. Alessio Cantore, group leader at SR-TIGET and Associate Professor at Vita-Salute San Raffaele University, who supervised and coordinated the study, stated, “We are confident that this study, together with other previous studies from our group at SR-TIGET, provides a comprehensive pre-clinical data package enabling the initiation of clinical testing in pediatric patients affected by MMA.” Genespire is progressing its lead asset for MMA, GENE202, towards the clinic.
