Krabbe disease (Globoid-cell leukodystrophy, GLD) is an inherited childhood disease caused by a deficiency in
the lysosomal enzyme, galactosyl-ceramidase (GALC). In the absence of GALC activity a highly cytotoxic
lipid, galactosyl-sphingosine (psychosine, Psy) accumulates and preferentially causes the death of
oligodendrocytes. Krabbe disease affects the central (CNS) and peripheral nervous systems (PNS) leading to
irritability, sensory deterioration, motor defects, seizures, and cognitive deficits beginning at 6 months of age
and death occurs by 2-5 years of age. There is currently no effective therapy for Krabbe disease. In
addition, all the evidence from years of research in authentic animal models of Krabbe disease shows that no
single treatment provides meaningful long-term benefits. However, we recently showed that a combination
therapy approach that simultaneously targets the primary pathogenic mechanism (GALC deficiency) and
secondary consequences of GALC deficiency (psychosine accumulation, inflammation, etc) dramatically and
synergistically increases efficacy. Although Krabbe disease was described over 100 years ago and the murine
model has been available for nearly 40 years, we know surprisingly little about the pathogenesis of the
disease. This is largely to the confounding effects of cross-correction. We have created a chimeric form of
GALC that retains enzyme activity, prevents the accumulation of psychosine and is incapable of cross-
correcting surrounding cells. This novel reagent will now enable us to determine both the contribution of cross-
correction to various therapeutic strategies and the role of specific cell types in the pathogenesis of Krabbe
disease. The goals of this proposal are to 1) determine the efficacy of newly developed substrate reduction
therapy drugs alone and in combination, 2) determine the mechanism/s by which certain therapies interact to
synergistically increase efficacy, 3) determine the role of specific cell types in the pathogenesis of Krabbe
disease, and 4) determine the mechanism/s by which psychosine is generated and potentially uncover a new
substrate reduction target. We will accomplish these goals with the following Specific Aims:
Aim 1: We will determine the therapeutic efficacy of a CGT-specific SRT drug, BMNS202, alone and in
combination with HSCT and AAV-mediated gene therapy.
Aim 2: We will determine the role of HSCT in the synergy observed when combined with CNS-directed AAV-
mediated gene therapy in the murine model of Krabbe disease.
Aim 3: We will determine the role of specific cell types in the pathogenesis of Krabbe disease.
Aim 4: We will determine the role of acid ceramidase in the catabolic production of psychosine and the
pathogenesis of Krabbe disease.