About Our Research

Therapeutic Approaches for Lysosomal Storage Diseases

Dr. Maegawa’s research laboratory has been devoted to developing therapeutic strategies for lysosomal storage diseases (LSDs), inborn organelle diseases caused by mutation in genes encoding mostly enzymes that are essential for lysosomes to function as units of compartmental recycling and degradation. From a clinical standpoint, patients suffering from LSDs present involvement of multiple organs and systems, predominantly the central nervous system. From a cellular and molecular perspective, a lysosomal enzyme deficiency results in the accumulation of primary and secondary natural substrates (Walkley 2009; Maxfield 2014). The lysosomal enlargement and dysfunction disturb several molecular pathways ultimately resulting in cell death. In a recent neonatal screening pilot study, the incidence of these conditions showed to be just over 1/2,000 (Mechtler, Stary et al. 2012). Only 8 amongst the nearly 60 LSDs have specific-FDA approved therapeutic agents. Several approaches have been developed over the years to treat LSDs (Fig.1). Currently, the enzyme replacement agents that are efficacious and safe, however unable to cross the blood-brain barrier and therefore restricted to treat non-neurological symptoms.

Based on the molecular pathogenesis of LSDs, the main focus of my research is to develop novel therapies that efficaciously alter the course of the progressive neurodegeneration typically observed in affected patients. Since my early clinical training until present, I have become interested in bringing novel therapeutic approaches to patients we diagnose, manage and follow with numerous LSDs. In the clinical arena, in contrast to most pediatric and adult common diseases, we have very few options in our therapeutic arsenal, which is often based on supportive care consisting of treatment of acute and chronic complications that are so common in LSDs and other inborn errors of metabolism. From a basic science perspective, the identification and characterization of molecular probes for specific targets, may not only generate drug candidates, but also potentially unravel novel molecular pathways involved in enzyme folding, translocation and maturation, ultimately improve our understanding of cellular protein homeostasis.

Our Research

Research Interests

The research in my lab is focused on developing new therapies of lysosomal storage diseases (LSDs) based on the understanding of molecular mechanisms of the pathogenesis of these diseases. These inherited metabolic conditions are caused by defects in a wide spectrum of lysosomal and a few non-lysosomal proteins resulting in accumulation of undigested substrates, resulting in dysfunction of lysosomal/endosomal system. The almost 60 different LSDs are individually rare genetic conditions, but, collectively, the incidence is approximately 1/2,000-3,000 live births. Since lysosomal/endosomal system is essential for cell homeostasis, this “inborn organelle disorders” results in multi-systemic diseases, and predominantly affecting the brain. The study LSDs allowed the discovery of several biological processes including the discovery of mannose-6-phosphate targeting system and currently gives insights into neurodegenerative mechanism in Alzheimer and Parkinson’s diseases.

In LSDs, the development of clinical symptoms usually correlates with a level of residual deficient enzyme activity. In patients with late onset forms of LSDs, a residual lysosomal activity is a result of missense mutations, which partially preserves catalytic enzyme function but mostly impairs the early folding process in the ER. These mutant lysosomal enzymes do not reach its appropriate conformation, and subsequently are directed to ER-associate degradation (ERAD) pathway, and are ultimately degraded by the ubiquitin-proteosome system. In this context, small molecule therapeutics are an attractive approach to treat LSDs. Enzyme-enhancement agents, including pharmacological chaperones (PC), are small molecules which are able to assist a mutant misfolded protein to achieve a native-like conformation in the endoplasmic reticulum (ER), allowing it to escape the ERAD pathway, and reach the lysosome. An advantage of this approach is that small molecules are much more likely to cross the blood brain barrier and reach neuronal cells, which are dramatically affected in LSDs. In addition, principles learned in treating one type of LSD can be applied not only to other LSDs, but also to other misconformation protein diseases, which is also feature of common neurodegenerative conditions.