A single intravenous infusion of a shielded lentiviral vector has corrected the root cause of methylmalonic acidemia in mice for their entire lifespan, raising hope for a one-time treatment for the devastating inherited metabolic disorder that currently has no approved drug therapy. The preclinical results, published in the Journal of Hepatology, emerge from a collaboration between Italian biotech company Genespire and the San Raffaele Telethon Institute for Gene Therapy in Milan, and they pave the way for clinical trials in children.
Methylmalonic acidemia, or MMA, is a rare genetic disease most often caused by mutations in the MMUT gene, which carries the blueprint for the mitochondrial enzyme methylmalonyl-CoA mutase. Without a working copy, the body cannot break down certain amino acids, odd-chain fatty acids, and cholesterol. Toxic methylmalonic acid accumulates in the blood and tissues, triggering metabolic crises, neurological damage, kidney failure, and drastically shortened life expectancy. Current management relies on strict dietary protein restriction and the use of carnitine supplements, measures that reduce but never eliminate the risk of decompensation. The constant threat of brain injury weighs heavily on families, and liver transplantation, while partially corrective, carries lifelong immunosuppression risks and does not fully normalize metabolites in all patients. A safe, durable genetic remedy has remained elusive.
The new approach circumvents a major obstacle that has plagued liver-directed gene therapy: the need to correct a sufficiently broad swath of hepatocytes without provoking a dangerous immune response against the vector or the transgene product. The team deployed an immune-shielded lentiviral vector (ISLV) engineered to resist destruction by the complement cascade and pre-existing antibodies—immune defenses that often neutralize standard viral vectors before they can reach the liver. By cloaking the lentivirus, the researchers enabled efficient intravenous delivery directly to the hepatic tissue. Once inside hepatocytes, the vector delivered a functional MMUT gene, restoring the missing enzyme precisely where the body’s metabolic detoxification machinery normally resides.
In a well-characterized mouse model of MMA that recapitulates the human disease’s biochemical and clinical hallmarks, a single systemic injection of the original vector produced sustained metabolic correction that persisted for the average lifespan of laboratory mice. Crucially, the animals were treated when young, before full liver maturation, and the therapeutic effect endured through postnatal liver growth and the dramatic hepatocellular proliferation that accompanies it. This durability suggests that the vector stably integrated into the genome of a sufficient number of liver cells and that those cells were not lost over time.
The researchers then pushed efficacy further by engineering an optimized version of the MMUT transgene. This refined construct delivered a dose-dependent improvement of metabolomic biomarkers, with gene transfer efficiency exceeding 80 percent of the liver. Circulating methylmalonic acid plummeted, secondary metabolic derangements normalized, and body weight trajectories recovered. The high efficiency and tunability of the optimized vector offer clinicians a potential path to tailor dosing according to disease severity, a critical consideration in pediatric populations.
One of the study’s most intriguing observations lies in the natural selection of corrected hepatocytes. Over time, the genetically healthy liver cells appeared to outcompete and replace their diseased neighbors, a phenomenon previously noted in other metabolic liver diseases but now documented in MMA with a lentiviral platform. This means that even a submaximal initial engraftment might progressively improve therapeutic efficacy as the liver regenerates, effectively amplifying the benefit of a single, lower-dose infusion. The molecular drivers of this selective advantage are not yet fully understood, but the result is a liver that gradually enriches its own metabolic capacity.
“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, CEO of Genespire. She confirmed that the company is advancing its lead candidate, GENE202, toward the clinic for MMA. Alessio Cantore, group leader at SR-TIGET and senior author of the study, added that the comprehensive preclinical data package, combined with earlier work from his group, strongly supports initiating clinical testing in pediatric patients.
The implications extend beyond a single disease. The ability to achieve lifelong hepatic correction through intravenous delivery of an immune-shielded lentiviral vector creates a platform approach for dozens of inborn errors of metabolism where the liver plays a central role. Unlike ex vivo gene therapies that extract, modify, and reinfuse a patient’s own cells, an off-the-shelf IV injection could be administered at any hospital equipped for pediatric infusions, dramatically widening accessibility. Genespire, a spin-out of SR-TIGET founded by gene therapy pioneer Luigi Naldini and Cantore, is betting that immune-shielded lentiviruses will become the chassis of choice for liver metabolic diseases. With GENE202 now approaching the clinic, the coming years will determine whether the mouse data translates into a long-awaited cure for children born with MMA.
Subject of Research: Animals
Article Title: Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice
News Publication Date: [Not available]
Web References: 10.1016/j.jhep.2026.05.011; Genespire
References: Journal of Hepatology, DOI: 10.1016/j.jhep.2026.05.011
Image Credits: San Raffaele-Telethon Institute for Gene Therapy
Keywords
methylmalonic acidemia, gene therapy, lentiviral vector, liver-directed, immune shielding, MMUT gene, metabolic disease, pediatric, preclinical, single administration, hepatocyte correction, ISLV
