Lentiviral Hematopoietic Stem and Progenitor Cell Gene Therapy for Metachromatic Leukodystrophy (MLD): Clinical Outcomes from 38 Patients

Background/Purpose: MLD is a fatal demyelinating lysosomal storage disease resulting from arylsulfatase A (ARSA) deficiency.

Methods: Thirty-eight patients with MLD (20 late-infantile [LI], 18 early juvenile [EJ]) were treated with hematopoietic stem and progenitor cell-based gene therapy (atidarsagene autotemcel, “arsa-cel”). Arsa-cel consists of autologous CD34+ cells transduced ex vivo with a lentiviral vector encoding for the functional human ARSA gene. Twenty-nine patients were treated with a fresh formulation and nine with a cryopreserved formulation, with follow-up from 0.08 to 7.9 years. Following myeloablative busulfan conditioning, arsa-cel was administered intravenously. Key endpoints were compared to an untreated natural history (NH) cohort.

Results: Of 38 patients treated, 35 are alive (2 died from disease progression, 1 from cerebral stroke, all unrelated to treatment). There were no treatment-related mortality or serious adverse events, and no malignancies, abnormal clonal expansion, or evidence of replication-competent lentivirus. All patients achieved hematologic recovery. Stable engraftment of gene-corrected cells and restoration of ARSA activity in the hematopoietic system and CSF was observed in 33 patients with ≥3 months follow-up. Most pre-symptomatic patients displayed long-term stabilization of motor function, with many maintaining walking capabilities, and normal cognitive development. Severe motor impairment-free survival was significantly longer in patients treated with the fresh formulation versus the NH cohort (LI: p < 0.001; EJ: p = 0.016).

Conclusion: Data from 38 early-onset MLD patients with up to 7.9 years of follow-up demonstrated that arsa-cel was generally well-tolerated and effective in modifying the disease course of early-onset MLD patients. Atidarsagene autotemcel (trade name: Libmeldy) was approved by the European Medicines Agency in 2020.

Publication History

Article published online:
28 October 2021