New therapeutic approaches for Krabbe disease: the potential of pharmacological chaperones

Abstract

Missense mutations in the lysosomal hydrolase β-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). The majority of these missense mutations are predicted to disrupt the fold of the enzyme, preventing sufficient amounts of GALC from reaching its site of action in the lysosome. The predominant central nervous system pathology and absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical need for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. To date, a number of small molecule inhibitors have been identified as promising chaperone candidates for GALC. Here we review and discuss the new insights gained from these studies and highlight the importance of characterizing both the chaperone interaction and the underlying mutation in order to properly define a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the need to use multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics such as proteasomal inhibition, which have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design provides a promising outlook for the development of KD therapeutics.