Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

TLDR

Metachromatic leukodystrophy is an inherited lysosomal storage disorder caused by ARSA deficiency that leads to progressive motor and cognitive decline and death within a few years of symptom onset. The study employed a lentiviral vector to introduce a functional ARSA gene into hematopoietic stem cells from three presymptomatic late‑infantile MLD patients. Reinfusion of the gene‑corrected HSCs produced stable, widespread ARSA expression in blood lineages and cerebrospinal fluid, showed no clonal abnormalities, and prevented disease onset or progression for 7–21 months beyond the expected age of symptom onset, demonstrating the therapeutic potential of lentiviral hematopoietic gene therapy for MLD.

Abstract

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.