Krabbe disease: New hope for an old disease

Abstract

Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by six months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the toxic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in pre-symptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.

Keywords: Gene therapy; Globoid cell leukodystrophy; Krabbe disease; Lysosomal storage disease.

Fig. 1.. Critical Milestones in our Understanding and Treatment of Krabbe disease.

Although not exhaustive, this is a timeline showing a brief history of Krabbe disease, critical milestones in our understanding of the disease, the identification of animal models, and the evolution of single and multimodal therapies. The superscript numbers associated with each milestone identifies a reference/s associated with the first example of each finding.

Fig. 2.. Synergistic Effects of Combination Therapies for Krabbe disease.

Kaplan-Meier curves of treated and untreated Twitcher and wild type mice. These data are compiled from several published studies from a single laboratory using identical reagents. Therefore, these life span curves can be directly compared. Twitcher mice treated with a combination of therapies survived significantly longer than those treated with any single therapy. The median life spans of untreated, BMT-treated, AAV5-treated, and L-cycloserine-treated (SRT) Twitcher mice are 39.5, 40.5, 71, and 58 days, respectively. If the combination of BMT and AAV5 (Twi AAV2/5 + BMT) were additive, the predicted median life span would be 70–75 days. However, the median life span for Twi AAV2/5 + BMT mice is ~120 days. If the effects of combining SRT (L-Cyc) with AAV5 + BMT (Twi AAV2/5 + BMT + L-Cyc) were additive, the predicted median life span would be 135–140 days. In actuality, the median life span of Twi AAV2/5 + BMT + L-Cyc mice is ~300 days. Alone, L-Cycloserine increases the life span of Twitcher mice by ~18 days. When added to AAV5 and BMT, L-Cycloserine adds an additional ~175 days to the median life span; clearly synergistic.

Fig. 3.. A Unifying Theory to Understand Psychosine Pathogenic Mechanism: Disruption of Lipid Raft Architecture and Function.

The lipid raft microdomain theory provides a powerful platform to start understanding how psychosine triggers a broad spectrum of downstream pathogenic responses. Under physiological conditions (Panel A), sterols such as cholesterol and glycosphingolipids such as sphingomyelin, gangliosides, sulfatides and galactosylceramides tend to coalesce in more rigid lipid microdomains (also known as rafts). These domains provide platforms where multiple other components such as scaffolding proteins, receptors, etc participate in cell signalling, can interact with optimal efficiency. When GALC activity is present, psychosine homeostasis is maintained. In contrast, psychosine remains undegraded in the absence of sufficient GALC activity as observed in Krabbe disease (Panel B). Consequently, psychosine accumulates to toxic levels in lipid rafts, modifying fluidity and lateral mobility of raft-associated components. The figure illustrates the example of how psychosine interferes with the IGF-PIP3-AKT pathway in neurons [92]. Although the components of the IGF pathway remain essentially unaltered in Krabbe disease, psychosine accumulation in rafts deforms and alters the chemical composition of these microdomains, impeding the association of raft components and transduction of the AKT signal to the cytosol. In panel C, the application of this unifying raft theory facilitates our understanding of how psychosine may alter other unrelated pathways (e.g. Notch, EGF, PDGF, complement, and neurotransmitter receptors) impacting on distinct cellular aspects from membrane shedding [103] to myelin stability [104] to neuronal/synaptic function [94].