Genespire and researchers at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) have published preclinical data supporting a liver-directed gene therapy approach for methylmalonic acidemia (MMA), a rare inherited metabolic disorder.

The study, published in the Journal of Hepatology, evaluated an immune-shielded lentiviral vector (ISLV) designed to deliver the MMUT gene to liver cells. Researchers found that a single systemic administration produced sustained improvements in disease features in a mouse model of MMA, with effects lasting throughout the animals’ lifespans.

MMA is caused by a deficiency of methylmalonyl-CoA mutase, an enzyme involved in breaking down proteins and fats from food. Without functional levels of this enzyme, toxic metabolites accumulate in the body, contributing to metabolic crises, impaired growth, neurological complications and damage to organs including the liver and kidneys.

In the study, researchers tested an optimised version of the MMUT gene delivered through the lentiviral vector system. The treatment resulted in dose-dependent improvements in metabolic biomarkers, with gene transfer efficiency exceeding 80% of liver cells in the mouse model.

The researchers also reported that genetically corrected liver cells may gradually replace diseased cells over time, suggesting that therapeutic effects could potentially increase after treatment.

Genespire is developing its lead programme, GENE202, as a potential single-administration gene therapy for MMA. The company said the preclinical findings support further development towards clinical testing.

Lucia Faccio, CEO of Genespire, said: “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.”

Faccio added: “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.”

Alessio Cantore, group leader at SR-TIGET and associate professor at Vita-Salute San Raffaele University, said the research provides further evidence supporting the potential clinical development of the approach.

“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,” Cantore said.

MMA is a rare genetic disorder most commonly caused by mutations affecting the MUT gene, which encodes the methylmalonyl-CoA mutase enzyme. Current treatment options focus on managing symptoms, as there are currently no approved disease-targeted therapies for the condition.

Genespire’s technology uses immune-shielded lentiviral vectors designed for intravenous delivery, with the aim of enabling long-term production of therapeutic proteins directly from liver cells. The company was founded as a spin-out from SR-TIGET and is initially focused on inherited metabolic diseases affecting children.

The study adds to ongoing research into gene therapies designed to address genetic disorders by replacing or correcting faulty genes rather than managing symptoms. Further clinical studies will be needed to determine whether the approach can provide similar benefits in people living with MMA.