CGT and ACD Inhibitors for SRT Treatment of Krabbe Disease

SUMMARY
Krabbe disease (KD) is caused by the deficiency of the ubiquitously expressed lysosomal enzyme
galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and
galactosylsphingosine (psychosine). Because the synthetic pathway conducing to psychosine is not affected in
KD, psychosine is continuously produced and accumulated in the Krabbe nervous system. Toxic levels of
psychosine are considered the main pathogenic trigger of disease. Currently, the standard of care for KD is
hematopoietic stem cell transplantation (HSCT), which is only applicable to asymptomatic or early symptomatic
infantile KD cases and only protracts disease. Pre-clinical gene therapy studies using adeno-associated viral
(AAV) vectors have shown great promise and in fact, AAV gene therapy applied early in life increases survival,
improves quality of life, and decreases neuropathology in twitcher (twi) mice, the natural model for KD. Based
on these important successes, AAV-based gene therapy clinical trials are being started only for infantile KD.
However, despite the prevention of significant disease-related deficits, HSCT and pre-clinical AAV-gene
therapy trials show varied long-term efficacy and resurgence of neurological disease.
Thus, the status of gene therapy for KD, the limitations of HSCT to treat primarily presymptomatic infantile
KD and the fact that juvenile and adult onset KD patients, which encompass a significant fraction of Krabbe
patients, largely remain without any treatment, highlight the need to develop additional strategies to sustain
long-term protection for KD patients. The use of substrate reduction therapies (SRT) strategies, singly or
combined with current and new therapies for KD, is one potential way to achieve this. In this application we will
use two small new compounds which selectively inhibit ceramide galactosyltransferase (CGT) and acid
ceramidase (ACD), enzymes that mediate the production of psychosine via galactosylation of ceramides and
sphingosine (CGT) and deacylation of galactosylceramide (ACD). Based on the premise that reducing
psychosine synthesis will prevent/reduce psychosine-related pathology at early postnatal development of the
mammalian brain, we will test the efficacy of SRT of CGT and ACD to enhance HSCT and AAV-GALC gene
therapy in the mouse model of infantile KD (twitcher mouse) and the efficacy of single treatment with
CGT or ACD inhibitors to ameliorate/prevent disease in a new model of adult-onset KD.

Grant Number: 5R01NS127403-04
NIH Institute/Center: NIH
Principal Investigator: Ernesto Bongarzone