Combined gene/cell therapies provide long-term and pervasive rescue of multiple pathological symptoms in a murine model of globoid cell leukodystrophy

Hum Mol Genet. 2015 Jun 15;24(12):3372-89. doi: 10.1093/hmg/ddv086. Epub 2015 Mar 5.


Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by deficient activity of β-galactocerebrosidase (GALC). The infantile forms manifest with rapid and progressive central and peripheral demyelination, which represent a major hurdle for any treatment approach. We demonstrate here that neonatal lentiviral vector-mediated intracerebral gene therapy (IC GT) or transplantation of GALC-overexpressing neural stem cells (NSC) synergize with bone marrow transplant (BMT) providing dramatic extension of lifespan and global clinical-pathological rescue in a relevant GLD murine model. We show that timely and long-lasting delivery of functional GALC in affected tissues ensured by the exclusive complementary mode of action of the treatments underlies the outstanding benefit. In particular, the contribution of neural stem cell transplantation and IC GT during the early asymptomatic stage of the disease is instrumental to enhance long-term advantage upon BMT. We clarify the input of central nervous system, peripheral nervous system and periphery to the disease, and the relative contribution of treatments to the final therapeutic outcome, with important implications for treatment strategies to be tried in human patients. This study gives proof-of-concept of efficacy, tolerability and clinical relevance of the combined gene/cell therapies proposed here, which may constitute a feasible and effective therapeutic opportunity for children affected by GLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Axons / metabolism
  • Axons / pathology
  • Bone Marrow Transplantation
  • Brain / metabolism
  • Cell Differentiation
  • Cell- and Tissue-Based Therapy*
  • Central Nervous System / metabolism
  • Central Nervous System / physiopathology
  • Disease Models, Animal
  • Enzyme Activation
  • Galactosylceramidase / genetics*
  • Galactosylceramidase / metabolism
  • Genetic Therapy*
  • Gliosis / genetics
  • Gliosis / metabolism
  • Gliosis / pathology
  • Graft Survival
  • Humans
  • Leukodystrophy, Globoid Cell / diagnosis
  • Leukodystrophy, Globoid Cell / genetics*
  • Leukodystrophy, Globoid Cell / metabolism
  • Leukodystrophy, Globoid Cell / mortality
  • Leukodystrophy, Globoid Cell / therapy
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myelin Sheath / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Peripheral Nervous System / metabolism
  • Peripheral Nervous System / physiopathology
  • Stem Cell Transplantation


  • Galactosylceramidase