Gene Therapy Reverses Peripheral Neuropathy Progression in Pre-Symptomatic LI-MLD Patients

Photo Credit: iStock.com/nopparit

Findings of a recent post-hoc analysis, which was presented at PNS 2025, demonstrated the efficacy of the gene therapy atidarsagene autotemcel (arsa-cel) in reducing the severity and progression of peripheral neuropathy in patients with late-infantile metachromatic leukodystrophy (LI-MLD).

The study, led by Alberto Zambon, MD, PhD, University of Padua, and colleagues, analyzed data from prospective open-label, single-arm interventional trials and expanded access programs involving pre-symptomatic patients treated with arsa-cel. This therapy involves a single infusion of the patient’s own genetically modified hematopoietic stem cells, designed to deliver supraphysiological levels of the arylsulfatase A (ARSA) enzyme, which is deficient in MLD.

The study followed patients over time using nerve conduction studies (NCSs) that measured the function of both motor (ulnar and deep peroneal) and sensory (median and sural) nerves. These data were compared with a control group of untreated patients, known as NHx, who were assessed using the same standardized protocol. The primary measure was nerve conduction velocity (NCV), a marker of demyelinating neuropathy. An exploratory endpoint included histopathologic changes in dermal nerve biopsies.

Among 15 treated and 16 untreated patients, the study found that treated individuals had significantly higher NCVs—by about 15 meters per second in motor nerves—at 36 months of age compared to age-matched controls. Most treated patients already exhibited neuropathy at the time of therapy (ages 7.3–17.4 months); however, the severity of neuropathy before treatment did not affect NCV outcomes two years after therapy. Importantly, younger age at treatment was associated with better NCV results, suggesting early intervention helps preserve nerve function.

ARSA enzyme levels measured in CD15+ myeloid cells also correlated positively with NCV outcomes, particularly in the deep peroneal nerve, and were linked to slower progression or slight improvements in nerve function over time. These findings imply that arsa-cel may offer superior benefits in peripheral nerve preservation compared to traditional allogeneic stem cell transplantation, likely due to its higher ARSA expression.

“In summary, peripheral neuropathy assessed by NCV is significantly ameliorated in LI patients treated with arsa-cel compared to untreated patients of similar age,” Dr. Zambon and colleagues concluded.

“In addition to the potential role of early age at treatment in the preservation of myelin, supraphysiological ARSA levels may slow demyelination of the DPN and other peripheral nerves. Arsa-cel may exert a stronger effect on NCV than allogeneic hematopoietic stem cell transplantation due to its greater ARSA expression.”