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). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the 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 requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small‐molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using 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, that 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. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

“…On the other hand, the alkaloid α-lobeline was identified as an allosteric PC for GALC. This molecule increased the enzyme's activity on a neuronal cell line with the GALC mutation p.D528N, while no effect was observed in other tested mutations [63,65]. Similar results were observed in fibroblasts from Krabbe disease patients treated with the allosteric PC α-lobeline and 3 4 7-trihydroxyisoflavone [25,63].…”

“…This compound showed a 98% inhibition of β-galactocerebrosidase (GALC) with a half maximal inhibitory concentration (IC 50 ) of 1 µM. However, this molecule lacks selectivity, as it was also able to inhibit lysosomal β-galactosidase [62,63]. N-ocytl-4-epi-b-valienamine (NOEV) was tested in cells from Krabbe disease patients, but the use of this compound as PC for Krabbe disease treatment remains unclear [63,64].…”

“…However, this molecule lacks selectivity, as it was also able to inhibit lysosomal β-galactosidase [62,63]. N-ocytl-4-epi-b-valienamine (NOEV) was tested in cells from Krabbe disease patients, but the use of this compound as PC for Krabbe disease treatment remains unclear [63,64]. On the other hand, the alkaloid α-lobeline was identified as an allosteric PC for GALC.…”

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

“…Newly synthesized GALC is co-translationally translocated into the ER and glycosylated in the Golgi apparatus (Spratley and Deane, 2016). GALC is then recognized by the mannose-6-phosphate receptor, which targets it to the lysosome either directly from the trans-Golgi network or indirectly via secretion and re-uptake (Nagano et al, 1998; Spratley and Deane, 2016).…”

“…GALC is then recognized by the mannose-6-phosphate receptor, which targets it to the lysosome either directly from the trans-Golgi network or indirectly via secretion and re-uptake (Nagano et al, 1998; Spratley and Deane, 2016). Once in the lysosome, GALC is cleaved into 50 and 30 KDa subunits and processes its lipid substrates.…”