Genespire Presents Promising Preclinical Data on Liver-Directed Gene Therapy for MMA at ASGCT 2025

Genespire presented positive preclinical data on dosing for its first-in-human, in vivo liver-directed gene therapy for methylmalonic acidemia (MMA) during an oral presentation at the 28th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Baltimore, Maryland. The therapy offers an off-the-shelf gene therapy solution for pediatric patients with genetic diseases. The presentation took place as part of the ongoing ASGCT Annual Meeting 2025.

Preclinical Study on Immune-Shielded Lentiviral Vectors Shows Promising Results and Potential for Human Clinical Trials

At the 28th Annual Meeting of the ASGCT, researchers presented findings on an immune-shielded lentiviral vector (ISLV) encoding a human MUT transgene, administered intravenously in a mouse model of methylmalonic acidemia (MMA). The therapy successfully delivered a functional MMUT gene to liver cells, resulting in effective treatment outcomes. A codon-optimized version, ISLV.MMUTco, demonstrated greater efficacy at lower doses compared to the wild-type vector. Researchers observed dose-dependent improvements across three dosing levels, with even the lowest dose producing therapeutic benefits due to the selective advantage of genetically corrected cells.

The study also used humanized mouse models to evaluate dosing strategies relevant for clinical translation. Results indicated that CD47-enriched vectors maintained therapeutic efficacy at significantly reduced doses, offering a potential path to safer and more efficient treatment in humans. These preclinical findings provide a strong foundation for advancing ISLV-based gene therapy into clinical trials for MMA.

Dr. Elena Barbon, Research Scientist, and Professor Alessio Cantore, Group Leader, conducted the study at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) in collaboration with Genespire. Professor Alessio Cantore, Group Leader at SR-TIGET and co-founder of Genespire, provided commentary on the findings by stating, “We are very proud to have secured another oral presentation slot at the highly respected ASGCT conference. These interesting data provide us with further preclinical validation on our integrative immune shielded lentiviral vector (LV)-based gene therapy as we progress toward the clinic.”

MMA Incidence Rates Show Variability Across Regions with 1 in 50,000 in Japan & 1 in 85,000 in Taiwan

Methylmalonic acidemia (MMA) is a rare genetic metabolic disorder primarily caused by mutations in the gene encoding the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). The condition impairs the body’s ability to process certain proteins and fats, leading to the accumulation of methylmalonic acid, which can damage the brain, liver, kidneys, and other organs. 

Estimates of methylmalonic acidemia (MMA) incidence vary by region, with reported rates of 1 in 50,000 in Japan, 1 in 250,000 in Germany, and 1 in 85,000 in Taiwan. Currently, no disease-targeted therapies are approved for MMA. Management primarily relies on dietary restrictions, including low-protein diets to limit the intake of certain amino acids, and supportive treatments such as carnitine supplementation or intermittent dialysis to reduce toxic metabolite buildup. However, these approaches only mitigate symptoms and do not address the underlying genetic defect.

Clinicians may consider liver or combined liver-kidney transplantation in severe cases to stabilize metabolic function, but these procedures carry substantial risks and do not offer a cure. Researchers are actively exploring gene therapy as a promising approach to restore functional MMUT enzyme activity and provide a long-term solution. Several preclinical studies, including those involving lentiviral and AAV vectors, have shown potential in correcting the metabolic defect in animal models.

Karen Aiach-Pignet, Genespire’s CEO added, “These data will help determine the dosing level for our anticipated Phase I clinical trial of GENE202 next year”, She added, “It is an exciting time to work at Genespire. There is a real sense of momentum in developing in vivo gene therapies following the acquisition of EsoBiotec by AstraZeneca earlier this year which has attracted a lot of interest in our work.”

Author

Denisse Sandoval