Gene therapy shows durable correction of methylmalonic acidemia in preclinical study

A new gene therapy developed by Genespire in collaboration with researchers at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) has shown the potential to provide long-lasting treatment for methylmalonic acidemia (MMA), a rare inherited metabolic disorder for which there are currently no approved disease-targeted medicines.

The preclinical findings showed that a single administration of the experimental therapy produced sustained improvements in a validated mouse model of the disease, with benefits lasting throughout the average lifespan of laboratory mice. 

Researchers say the results support the potential of the liver-directed, immune-shielded lentiviral gene therapy to provide durable correction of the genetic defect underlying MMA while maintaining its effectiveness as the liver grows and matures after birth. 

Addressing a serious inherited condition

MMA is most commonly caused by mutations in the gene responsible for producing methylmalonyl-CoA mutase (MUT), a mitochondrial enzyme that enables the body to break down certain proteins and fats from food.

Without a functioning version of the enzyme, methylmalonic acid accumulates in the bloodstream, leading to progressive damage to the brain, liver, kidneys and other organs. Patients often experience severe complications, significant illness and a substantially reduced life expectancy.

The experimental treatment delivers a healthy copy of the MMUT gene using a lentiviral vector designed to target liver cells, with the aim of restoring normal metabolic function after a single treatment.

Improved gene delivery

During the study, researchers also tested an optimised version of the MMUT transgene. In the same mouse model, this enhanced approach produced dose-dependent improvements in metabolic biomarkers while achieving gene transfer in more than 80 percent of liver cells.

The findings also suggested that healthy, genetically corrected liver cells may gradually replace diseased cells over time, which could allow the treatment’s effectiveness to continue improving after administration, even when lower initial doses are used.

“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,” said Lucia Faccio, Chief Executive Officer 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. We would like to extend our gratitude to everyone involved in the research project, especially those at the SR-TIGET.”

Next step towards clinical trials

The study builds on previous research into lentiviral gene therapies and provides further evidence that liver-directed treatment could offer a durable solution for inherited metabolic diseases. 

Although the results are limited to animal studies, the researchers believe they represent an important milestone in the development of a therapy for children born with MMA.

“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,” said Dr Alessio Cantore, a group leader at SR-TIGET and Associate Professor at Vita-Salute San Raffaele University, who supervised and coordinated the study and signed it as senior author.

Further studies will be needed to confirm the therapy’s safety and effectiveness in people before it can progress through clinical development. However, the findings suggest that a single-dose gene therapy could eventually provide a long-term treatment option for patients living with this life-limiting inherited disorder.