Chaperones as potential therapeutics for Krabbe disease

Abstract

Krabbe's disease (KD) is an autosomal recessive, neurodegenerative disorder. It is classified among the lysosomal storage diseases (LSDs). It was first described in , but the genetic defect for the galactocerebrosidase (GALC) gene was not discovered until the beginning of the 1970s, 20 years before the GALC cloning. Recently, in 2011, the crystal structures of the GALC enzyme and the GALC-product complex were obtained. For this, compared with other LSDs, the research on possible therapeutic interventions is much more recent. Thus, it is not surprising that some treatment options are still under preclinical investigation, whereas their relevance for other pathologies of the same group has already been tested in clinical studies. This is specifically the case for pharmacological chaperone therapy (PCT), a promising strategy for selectively correcting defective protein folding and trafficking and for enhancing enzyme activity by small molecules. These compounds bind directly to a partially folded biosynthetic intermediate, stabilize the protein, and allow completion of the folding process to yield a functional protein. Here, we review the chaperones that have demonstrated potential therapeutics during preclinical studies for KD, underscoring the requirement to invigorate research for KD-addressed PCT that will benefit from recent insights into the molecular understanding of GALC structure, drug design, and development in cellular models. © 2016 Wiley Periodicals, Inc.

E-Learning for Rare Diseases: An Example Using Fabry Disease

“…FD represents a successful example of the use of pharmacological chaperones. This approach, which is definitely limited to a subset of missense mutations, is not limited to FD, and is being assessed with respect to other lysosomal [ 43 , 44 ] and metabolic disorders [ 45 , 46 , 47 , 48 ] as well.…”

Proteostasis network alteration in lysosomal storage disorders: Insights from the mouse model of Krabbe disease

“…To our knowledge, GALC mutation in TW mice leads to the loss of enzymatic activity probably due to nonsense-mediated mRNA decay (Graziano & Cardile, 2015;Kobayashi et al, 1980;Lee et al, 2006;Luddi et al, 2016;Potter et al, 2013). The loss of enzymatic activity inevitably leads to a progressive accumulation of psychosine that disrupts downstream biochemical pathways within the cell, and ultimately results in demyelination and cell death (Graziano et al, 2016). In particular, psychosine, retained the main pathological cause of Krabbe disease (Igisu & Suzuki, 1984), preferentially accumulates in lipid raft (LR) domains disrupting their architecture and composition even at 3 days after birth (Taniike & Suzuki, 1994).…”

“…Due to the high levels of GalCers in central and peripheral nervous system (CNS and PNS, respectively), GalCer and psycosine quickly accumulate in oligodendrocytes and Schwann cells and, according to their cytotoxicity, they lead to demyelination and axonopathy (Graziano & Cardile, 2015). Other approaches have been investigated in twitcher mouse (TW), the natural mouse model of Krabbe disease, including gene therapy, substrate reduction, chemical chaperons, and enzyme replacement therapy (Berardi et al, 2014;Graziano, Pannuzzo, Avola, & Cardile, 2016;Luddi, Crifasi, Capaldo, Piomboni, & Costantino-Ceccarini, 2016;Rafi et al, 2015). Different kinds of gene mutations not only lead to a unique protein defect, but also to a complex dysregulation of the entire PN that has to be extensively studied in order to find a therapeutic strategy to restore GALC and PN functions (Irahara-Miyana et al, 2018).…”

“…Currently, the standard of care for infant with Krabbe disease is nonspecific therapies, such as hematopoietic stem cell transplantation; positive effects have been obtained only in pre-symptomatic patients (Matthes et al, 2015) and little evidence has been observed in remyelination and reversion of neurological impairment (Graziano & Cardile, 2015). Other approaches have been investigated in twitcher mouse (TW), the natural mouse model of Krabbe disease, including gene therapy, substrate reduction, chemical chaperons, and enzyme replacement therapy (Berardi et al, 2014;Graziano, Pannuzzo, Avola, & Cardile, 2016;Luddi, Crifasi, Capaldo, Piomboni, & Costantino-Ceccarini, 2016;Rafi et al, 2015).…”

Opening New Horizons in the Treatment of Childhood Onset Leukodystrophies

“…Both strategies, separately or in combination, aim to result in at least partially active proteins with correct subcellular localizations. 69 The potential effectiveness of these compounds is now studied and discussed for numerous LDs like GLD 70 and PMD (►Fig. 1).…”