New paradigms for the treatment of lysosomal storage diseases: targeting the endocannabinoid system as a therapeutic strategy

Abstract

Over the past three decades the lysosomal storage diseases have served as model for rare disease treatment development. While these efforts have led to considerable success, important challenges remain. For example, no treatments are currently approved for nearly two thirds of all lysosomal diseases, and there is limited impact of the existing drugs on the central nervous system. In addition, the costs of these therapies are extremely high, in part due to the fact that drug development has focused on a "single hit" approach - i.e., one drug for one disease. To overcome these obstacles researchers have begun to focus on defining common disease mechanisms in the lysosomal diseases, particularly in the central nervous system, with the hope of identifying drugs that might be used in several lysosomal diseases rather than an individual disease. With this concept in mind, herein we review a new potential treatment approach for the lysosomal storage diseases that focuses on modulation of the endocannabinoid system. We provide a short introduction to lysosomal storage diseases and the endocannabinoid system, followed by a brief review of data supporting this concept.

Keywords: Endocannabinoids; Lysosomal storage diseases; Treatment.

Fig. 1

Effect of FAAH inhibition in ASMD. All pathology in ASMD is initiated by sphingomyelin (SPM) build-up. FAAH inhibition leads to the elevation of AEA and other endocannabinoids (ECs), resulting in the activation of CB1. This, in turn, activates neutral sphingomyelinase (NSM), which slows or prevents SPM buildup and the resulting downstream pathology and disease

Fig. 2

CB2 expression in tissues from Farber and MPS IIIA mice. CB2 is markedly overexpressed in the liver and CNS of mice with Farber disease and MPS IIIA. WT, wildtype; FD, Farber. Brown color indicates staining with CB2 antibodies. Blue color indicates cell nuclei. Bars = 50 µm