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

Abstract

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.

• Authors: 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
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 16 Pg. 6495-505 (Apr 22 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 25904800 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the authors 0270-6474/15/356495-11$15.00/0.

Chemical References

• Cytokines
• Psychosine
• Cycloserine
• Galactosylceramidase

Topics

• Animals
• Body Weight (drug effects, genetics)
• Bone Marrow Transplantation
• Brain (drug effects, metabolism)
• Combined Modality Therapy
• Cycloserine (therapeutic use)
• Cytokines (metabolism)
• Female
• Galactosylceramidase (genetics, metabolism)
• Genetic Therapy
• Leukodystrophy, Globoid Cell (drug therapy, genetics, pathology, therapy)
• Male
• Mice
• Mice, Inbred Strains
• Motor Skills (drug effects)
• Myelin Sheath (drug effects, physiology)
• Psychosine (metabolism)
• Sciatic Nerve (metabolism)