Therapeutic Approaches for Lysosomal Storage Diseases

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For the past years, my research laboratory has devoted to develop 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.