Early Gene Therapy Can Preserve Motor and Cognitive Functions in Children with Rare Neurodegenerative Disease

Recent research highlights the significant potential of early gene therapy to alter the progression of metachromatic leukodystrophy (MLD), a rare and often fatal neurodegenerative disorder affecting children. MLD results from genetic mutations that impair sulfatide metabolism, leading to dangerous accumulation in the central and peripheral nervous systems. Children with the most severe forms typically experience rapid loss of mobility, speech, and social interaction, with many succumbing in infancy. Annually, approximately 1 in 100,000 children worldwide is born with MLD.

A groundbreaking study published in the New England Journal of Medicine examined 39 children treated at the San Raffaele Hospital in Milan. The study demonstrated that early application of gene therapy could substantially preserve motor and cognitive functions. The therapy involves a single infusion of genetically corrected hematopoietic stem cells, following chemotherapy to prepare the body for the treatment. It gained approval in the European Union in 2020 and has been reimbursed in Italy since 2022. This success reflects over two decades of dedicated research by the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) and a strategic partnership with Orchard Therapeutics.

The study compared the outcomes of these treated children to 49 untreated patients, focusing on motor skills—such as walking or sitting unsupported—and cognitive abilities, including speech and developmental tests. Results showed that, over long-term follow-up, gene therapy markedly reduced the risk of severe motor and cognitive decline across various patient subgroups, including those with late-infantile and juvenile-early-onset forms. Children treated before symptom onset retained their ability to walk, unlike untreated children, who lost these skills within their first years. Additionally, most treated children continued to develop cognitively, acquiring new skills and maintaining communication abilities.

Experts emphasize the importance of early diagnosis for maximizing treatment benefits. Dr. Alessandro Aiuti stressed the necessity of implementing newborn screening programs to detect MLD before clinical signs appear. Since diagnosis is often delayed, early detection through neonatal screening could be a game changer, offering the possibility to intervene with gene therapy before irreversible damage occurs. Currently, MLD is not included in standard newborn screening panels globally, apart from pilot studies in Italy and Norway, but early identification could significantly improve outcomes.

MLD arises from mutations disrupting sulfatide breakdown, causing accumulation mainly in neural tissues. Severe forms lead to rapid neurological deterioration with limited treatment options, making gene therapy a promising approach. The therapy is indicated for children in pre-symptomatic stages or with mild initial symptoms, giving hope for altered disease trajectories.

In Italy, neonatal screening programs are expanding to include more genetic metabolic diseases, but MLD remains under investigation. Preliminary results from ongoing pilot projects have already diagnosed some cases early, opening pathways for timely interventions. As research continues, early gene therapy represents a beacon of hope for children affected by this devastating disease, emphasizing the critical need for early detection and swift action.