Abstract
Background: Metachromatic leukodystrophy (MLD) is an ultrarare, severe lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA).
Methods: We treated patients who had MLD with atidarsagene autotemcel (arsa-cel), a hematopoietic stem-cell-based gene therapy, in two prospective open-label clinical studies and expanded-access programs. We compared their outcomes with those of untreated patients (natural history cohort). The primary end point was survival free from severe motor impairment (the time from birth to the first occurrence of loss of locomotion and of sitting without support or death from any cause).
Results: A total of 39 treated patients and 49 untreated patients were included. The median follow-up was 6.76 years (range, 0.64 to 12.19). Arsa-cel resulted in a significantly lower risk of severe motor impairment or death than no treatment among patients with presymptomatic late-infantile MLD (P<0.001), those with presymptomatic early-juvenile MLD (P = 0.04), and those with early-symptomatic early-juvenile MLD (P<0.001). The estimated percentage of patients surviving without severe motor impairment at 6 years of age was 0% (95% confidence interval [CI], not evaluable) among untreated patients with late-infantile MLD and 100% (95% CI, 100 to 100) among treated patients with presymptomatic late-infantile MLD. The estimated percentage of patients surviving without severe motor impairment at 10 years of age was 11.2% (95% CI, 0.9 to 36.4) among untreated patients with early-juvenile MLD and 87.5% (95% CI, 38.7 to 98.1) and 80.0% (95% CI, 40.9 to 94.6) among treated patients with presymptomatic and early-symptomatic early-juvenile MLD, respectively. No evidence of insertional oncogenesis was found. The most common grade 3 or higher adverse event was febrile neutropenia. Anti-ARSA antibodies were detected transiently in 6 of 39 patients (15%). Three deaths occurred, all of which were considered by the investigators to be unrelated to arsa-cel.
Conclusions: Among patients with presymptomatic late-infantile or early-juvenile MLD and those with early-symptomatic early-juvenile MLD, the risk of severe motor impairment or death was significantly lower among those who received treatment with arsa-cel than in a natural history cohort that did not receive treatment.
Wolf NI, van der Knaap MS, Engelen M. Treatment of leukodystrophies: Advances and challenges. Eur J Paediatr Neurol. 2025 May;56:46-50. doi: 10.1016/j.ejpn.2025.03.016. Epub 2025 Apr 15. PMID: 40279833.
Abstract
Leukodystrophies, a group of genetic disorders primarily affecting brain white matter, were once considered untreatable. Advances in MRI and genetic diagnostics now allow most patients to receive a genetic diagnosis, and emerging treatments are shifting the field from therapeutic nihilism to cautious optimism. Allogenic haematopoietic stem cell transplantation (HSCT), used since the 1980s, has shown efficacy in specific leukodystrophies, such as adrenoleukodystrophy and metachromatic leukodystrophy, when administered early. Gene therapy has become a viable option, with ex vivo approaches like atidarsagene autotemcel providing promising outcomes for early-onset MLD. Trials for gene replacement and antisense oligonucleotide therapies are ongoing for several leukodystrophies, including Canavan disease and Alexander disease. Certain treatments, such as guanabenz for Vanishing White Matter, target disease-specific dysregulated molecular pathways. Despite these advances, challenges remain, including the ultrarare nature of most leukodystrophies, limited natural history data, high treatment costs, and barriers to accessibility. Future developments, including newborn screening and close international collaboration, aim to enhance early diagnosis, refine treatment timing, and expand access to innovative therapies.
Zambon AA, Rancoita PMV, Quattrini A, Butera C, Gentile F, Facchini M, Mazza S, Recupero S, Gallo V, Shenker A, Gollop ND, Del Carro U, Calbi V, Di Serio C, Natali Sora MG, Filippi M, Aiuti A, Fumagalli F. Effects of atidarsagene autotemcel gene therapy on peripheral nerves in late-infantile metachromatic leukodystrophy. Brain. 2025 Apr 26:awaf157. doi: 10.1093/brain/awaf157. Epub ahead of print. PMID: 40286327.
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.
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