Genespire and SR-TIGET Demonstrate Durable Preclinical Efficacy of Liver-Directed Gene Therapy for Methylmalonic Acidemia
核心洞察
A single systemic administration of an immune-shielded lentiviral vector encoding the MMUT (搜索) gene produced sustained therapeutic benefits lasting the average lifespan of laboratory mice in a validated MMA model.
Gene transfer efficiency exceeded 80% of the liver, with an optimized MMUT (搜索) transgene showing dose-dependent improvement of metabolomic biomarkers.
Genespire (搜索) is advancing its lead asset GENE202 toward clinical testing, with researchers confirming a comprehensive preclinical data package supports initiation of trials in pediatric patients.
MILAN — Genespire (搜索), in collaboration with researchers at the San Raffaele Telethon Institute for Gene Therapy (搜索) (SR-TIGET), has published preclinical data demonstrating that a single systemic administration of a liver-directed immune-shielded lentiviral vector (ISLV) encoding the MMUT (搜索) gene produced durable therapeutic benefits in a validated mouse model of methylmalonic acidemia (搜索) (MMA), a severe inherited metabolic disorder with no approved disease-targeted therapies.
The findings, published in the Journal of Hepatology, showed that treatment effects lasted for the average lifespan of laboratory mice. Because the mice were treated when young, the study supports the durability of the gene therapy through postnatal growth and maturation of the liver.
MMA is caused by a deficiency of methylmalonyl-CoA mutase (搜索), an enzyme critical to the body's metabolism of food. Its absence leads to the accumulation of toxic metabolites that cause recurrent metabolic crises, growth failure, neurological impairment, and multi-organ damage. Currently, no disease-targeted drugs are approved for MMA, and affected patients suffer high levels of morbidity and a heavily reduced life expectancy.
Optimized transgene and dose-dependent response
In the study, researchers treated mice with a dose containing an optimized MMUT (搜索) transgene, which improved therapeutic efficacy. This version exhibited a dose-dependent improvement of metabolomic biomarkers, with gene transfer efficiency exceeding 80% of the liver.
The study also highlighted that genetically corrected cells in the liver may, over time, replace the diseased ones, suggesting that therapeutic efficacy may progressively improve even when starting at lower initial doses.
Path toward the clinic
"Together, these findings indicate that Genespire (搜索) is on a clear path towards the long-term correction of metabolic diseases which impact the liver and other organs," said Lucia Faccio, CEO of Genespire. "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."
Dr. Alessio Cantore, group leader at SR-TIGET and Associate Professor at Vita-Salute San Raffaele University, who supervised and coordinated the study as senior author, added: "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 (搜索), a spin-out of SR-TIGET, is developing off-the-shelf immune-shielded lentiviral vector-based gene therapies for pediatric patients affected by genetic diseases. The ISLVs are designed for intravenous administration and enable life-long production of the therapy directly from the patient's liver.