RT Journal Article
SR Electronic
T1 Mechanism-Based Combination Treatment Dramatically Increases Therapeutic Efficacy in Murine Globoid Cell Leukodystrophy
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6495
OP 6505
DO 10.1523/JNEUROSCI.4199-14.2015
VO 35
IS 16
A1 Jacqueline A. Hawkins-Salsbury
A1 Lauren Shea
A1 Xuntian Jiang
A1 Daniel A. Hunter
A1 A. Miguel Guzman
A1 Adarsh S. Reddy
A1 Elizabeth Y. Qin
A1 Yedda Li
A1 Steven J. Gray
A1 Daniel S. Ory
A1 Mark S. Sands
YR 2015
UL http://www.jneurosci.org/content/35/16/6495.abstract
AB 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.