Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem

Abstract

Abstract Lysosomal storage diseases (LSDs) are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. Depending on the protein or enzyme deficiency associated with each disease, LSDs affect an array of organ systems and elicit a complex set of secondary disease mechanisms that make many of these disorders difficult to fully treat. The etiology of most LSDs is known and the innate biology of lysosomal enzymes favors therapeutic intervention, yet most attempts at treating LSDs with enzyme replacement strategies fall short of being curative. Even with the advent of more sophisticated approaches, like substrate reduction therapy, pharmacologic chaperones, gene therapy or stem cell therapy, comprehensive treatments for LSDs have yet to be achieved. Given the limitations with individual therapies, recent research has focused on using a combination approach to treat LSDs. By coupling protein-, cell-, and gene- based therapies with small molecule drugs, researchers have found greater success in eradicating the clinical features of disease. This review seeks to discuss the positive and negatives of singular therapies used to treat LSDs, and discuss how, in combination, studies have demonstrated a more holistic benefit on pathological and functional parameters. By optimizing routes of delivery, therapeutic timing, and targeting secondary disease mechanisms, combination therapy represents the future for LSD treatment.

Figure 1. Lysosomal storage diseases: pathological mechanisms and possibilities for therapeutic intervention

Lysosomal storage diseases (LSDs) are caused by a genetic mutation in lysosomal proteins that leads to enzyme or protein deficiencies. These deficiencies perturb lysosomal function resulting in intra-lysosomal substrate accumulation, lysosome distention, and lysosome proliferation. Alterations in lysosomal biology result in cellular dysfunction that ultimately affects a diverse set of organ systems. Moreover, there are secondary consequences of lysosomal dysfunction that increases cellular stress. Therefore, although the etiology of LSDs is well known and well characterized, no singular therapy for treating LSDs has been fully curative because of the multifarious set of disease mechanisms at play and the diverse set of organs involved. By using a combination of therapeutic approaches, targeting both primary and secondary mechanisms of disease in multiple organ systems, a more holistic approach to treating LSDs can be attained.