Researchers from Genespire and the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) presented promising preclinical data on dosing strategies for an in vivo liver-directed gene therapy for methylmalonic acidemia (MMA) at the 28th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Baltimore.
The oral presentation, delivered on May 13, 2025, detailed how intravenous administration of an immune-shielded lentiviral vector (ISLV) encoding the human MUT transgene effectively treated MMA in mouse models by delivering a functional MMUT gene to liver cells.
"These interesting data provide us with further preclinical validation on our integrative immune shielded lentiviral vector-based gene therapy as we progress toward the clinic," said Professor Alessio Cantore, Group Leader at SR-TIGET and co-founder of Genespire.
Key Findings on Vector Optimization and Dosing
The research team, led by Dr. Elena Barbon, Research Scientist at SR-Tiget, demonstrated that a codon-optimized version of the vector (ISLV.MMUTco) showed significantly higher efficacy at lower doses compared to the wild-type version. This optimization represents an important advancement in the development of more efficient gene therapy vectors.
Testing across three different dosing levels revealed dose-dependent improvements in disease markers, with evidence that even the lowest dose conferred therapeutic benefits. This effect appears to be driven by the selective advantage of treated hepatocytes, which proliferate preferentially over untreated cells in the MMA disease environment.
Particularly noteworthy were findings from humanized mouse models showing that CD47-enriched vectors achieved comparable efficacy at substantially lower doses. This could have significant implications for clinical dosing strategies, potentially reducing the amount of vector needed for therapeutic effect in humans.
Clinical Development Timeline
Karen Aiach-Pignet, Genespire's CEO, emphasized the importance of these findings for their clinical program: "These data will help determine the dosing level for our anticipated Phase I clinical trial of GENE202 next year."
She also noted growing industry interest in in vivo gene therapies following recent acquisition activity in the sector: "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."
ISLV Technology Platform
Genespire's proprietary immune-shielded lentiviral vectors (ISLVs) represent a novel approach to gene therapy delivery. These vectors are designed for intravenous administration, allowing for life-long production of therapeutic proteins directly from the patient's liver.
The company's lead candidate, GENE202, is advancing toward clinical development for the treatment of MMA, a devastating genetic disorder that currently lacks disease-targeted approved therapies.
Understanding Methylmalonic Acidemia
MMA is a rare genetic metabolic disorder most frequently caused by mutations in the gene coding for the mitochondrial enzyme methylmalonyl-coA mutase (MUT). Patients with MMA are unable to properly metabolize certain proteins and fats, resulting in the accumulation of methylmalonic acid in the body.
This accumulation causes progressive damage to multiple organs, particularly the brain, liver, and kidneys. Affected patients face significant morbidity and reduced life expectancy. Current management approaches focus on dietary restrictions and supportive care, highlighting the urgent need for disease-modifying therapies.
About Genespire
Founded in March 2020, Genespire is a Milan-based biotechnology company developing off-the-shelf gene therapies for pediatric patients with genetic diseases. The company was established by gene therapy pioneers Prof. Luigi Naldini and Dr. Alessio Cantore, along with the Fondazione Telethon and Ospedale San Raffaele.
As a spin-out of SR-Tiget, a world-leading cell and gene therapy research institute, Genespire is leveraging cutting-edge technology to address high unmet medical needs in inherited metabolic diseases. The company's initial focus is on developing ISLV-based therapies that can provide durable therapeutic benefit through liver-directed gene expression.
