Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy

Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.


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.

Trial registration: ClinicalTrials.gov NCT01560182.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / pathology
  • Cerebroside-Sulfatase / genetics*
  • DNA Damage
  • Follow-Up Studies
  • Genetic Engineering
  • Genetic Therapy / methods*
  • Genetic Vectors / toxicity
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Lentivirus
  • Leukodystrophy, Metachromatic / pathology
  • Leukodystrophy, Metachromatic / therapy*
  • Magnetic Resonance Imaging
  • Transduction, Genetic
  • Treatment Outcome
  • Virus Integration


  • Cerebroside-Sulfatase

Associated data

  • ClinicalTrials.gov/NCT01560182