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

Abstract

This study evaluates the efficacy of arsa-cel gene therapy (GT) 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). This is a post-hoc analysis conducted on pre-symptomatic patients affected by LI-MLD treated with ex vivo autologous hematopoietic stem cell GT (atidarsagene autotemcel, “arsa-cel”) in the context of prospective open-label, single-arm, interventional trials and expanded access programs. All patients were followed longitudinally with nerve conduction studies (NCSs) of peripheral motor (ulnar - UN, deep peroneal - DPN) and sensory (median - MN, sural - SN) nerves. These results were compared with those from a control group of untreated patients (NHx) studied with the same standardized protocol. We then analyzed the effects of baseline characteristics (age at treatment, severity of neuropathy pre-treatment expressed as age-matched NCV Z-scores) and arylsulfatase A (ARSA) enzyme activity (measured in peripheral blood myeloid CD15+ cells post treatment) on NCVs of treated patients. The primary endpoint of this post-hoc analysis was NCV, reflecting 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 (IQR) at treatment of 13 (9.1;14.5) months. At 36 months of age, treated patients showed higher estimated NCVs in all nerves compared to 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-GT, or on the rate of NCV slowing afterwards. A younger age at treatment was associated with higher NCVs of motor UN and sensory MN 2 years post-GT. Overall, ARSA levels in CD15+ cells correlated with NCVs of motor DPN at 2 years post-GT, and ARSA levels were associated with a slower decrease or a slight increase in NCVs of the DPN, UN and MN nerves afterwards. In summary, peripheral neuropathy assessed by NCV is significantly ameliorated in LI patients treated with arsa-cel compared to 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 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.