Effects of atidarsagene autotemcel gene therapy on peripheral nerves in late-infantile metachromatic leukodystrophy

This study evaluated the efficacy of atidarsagene autotemcel (arsa-cel) gene therapy in mitigating the severity and progression of peripheral neuropathy as assessed by nerve conduction velocity (NCV) in individuals affected by late-infantile metachromatic leukodystrophy (LI-MLD). A post hoc analysis was conducted on pre-symptomatic patients affected by LI-MLD treated with ex vivo autologous haematopoietic stem cell gene therapy (arsa-cel) in the context of prospective open-label, single-arm, interventional trials and expanded access programmes. All patients were followed longitudinally with nerve conduction studies (NCSs) of peripheral motor (ulnar, deep peroneal) and sensory (median, sural) nerves. These results were compared with those from a control group of untreated patients (NHx) studied with the same standardized protocol. We then analysed the effects of baseline characteristics (age at treatment, severity of neuropathy pre-treatment expressed as age-matched NCV Z-scores) and arylsulphatase A (ARSA) enzyme activity (measured in peripheral blood myeloid CD15+ cells post-treatment) on NCVs of treated patients. The primary end point of this post hoc analysis was NCV, reflecting the severity of demyelinating neuropathy. Changes in dermal nerve histopathology in skin biopsies were used as an exploratory outcome. Fifteen treated and 16 NHx patients were included in the analyses, with a median age (interquartile range) at treatment of 13 (9.1-14.5) months. At 36 months of age, treated patients showed higher estimated NCVs in all nerves compared with age-matched controls (∼15 m/s difference in motor nerves). Peripheral neuropathy was observed in the majority of treated patients at their pre-treatment examination (age range 7.3-17.4 months). Severity of pre-treatment neuropathy in treated patients did not have an effect on NCV values at 2 years post-gene therapy or on the rate of NCV-slowing afterwards. A younger age at treatment was associated with higher NCVs of motor ulnar nerve and sensory medial nerve 2 years post-gene therapy. Overall, ARSA levels in CD15+ cells correlated with NCVs of motor deep peroneal nerve at 2 years post-gene therapy, and ARSA levels were associated with a slower decrease or a slight increase in NCVs of the deep peroneal, ulnar and medial nerves afterwards. In summary, peripheral neuropathy assessed by NCV is significantly ameliorated in LI patients treated with arsa-cel compared with untreated patients of similar age. In addition to the potential role of early age at treatment in the preservation of myelin, supraphysiological ARSA levels may slow demyelination of the deep peroneal and other peripheral nerves. Arsa-cel may exert a stronger effect on NCV than allogeneic haematopoietic stem cell transplantation due to its greater ARSA expression.