Mechanism-based combination treatment dramatically increases therapeutic efficacy in murine globoid cell leukodystrophy

Jacqueline A. Hawkins-Salsbury, Lauren Shea, Xuntian Jiang, Daniel A. Hunter, A. Miguel Guzman, Adarsh S. Reddy, Elizabeth Y. Qin, Yedda Li, Steven J. Gray, Daniel S. Ory, Mark S. Sands

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates in the CNS and peripheral nervous system. Oligodendrocytes and Schwann cells are particularly sensitive to psychosine, thus leading to a demyelinating phenotype. Although hematopoietic stem-cell transplantation provides modest benefit in both presymptomatic children and the murine model (Twitcher), there is no cure for GLD. In addition, GLD has been relatively refractory to virtually every experimental therapy attempted. Here, Twitcher mice were simultaneously treated with CNS-directed gene therapy, substrate reduction therapy, and bone marrow transplantation to target the primary pathogenic mechanism (GALC deficiency) and two secondary consequences of GALC deficiency (psychosine accumulation and neuroinflammation). Simultaneously treating multiple pathogenic targets resulted in an unprecedented increase in life span with improved motor function, persistent GALC expression, nearly normal psychosine levels, and decreased neuroinflammation. Treating the primary pathogenic mechanism and secondary targets will likely improve therapeutic efficacy for other LSDs with complex pathological and clinical presentations.

Original languageEnglish (US)
Pages (from-to)6495-6505
Number of pages11
JournalJournal of Neuroscience
Issue number16
StatePublished - Apr 22 2015


  • Dysmyelination
  • Gene therapy
  • Globoid cell leukodystrophy
  • Krabbe disease
  • Lysosomal storage disease

ASJC Scopus subject areas

  • General Neuroscience


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