Our research lab is focus 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 (BBB) and reach neuronal cells, which are dramatically affected in LSDs. We are also using nanovesicles (exosomes) to deliver therapeutics through the BBB and treat this neuological 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.
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