IMPROVING THE THERAPEUTIC POTENTIAL OF LYSOSOMAL ENZYMES TO TREAT CNS IN LYSOSOMAL STORAGE DISORDERS

Lysosomal storage disorders (LSD) are a large group of inherited genetic diseases caused by impaired activity of lysosomal enzymes leading to accumulation of undigested macromolecules within the lysosomes and thus cell dysfunction. The clinical manifestation is heterogeneous and neurological involvement represents a major problem. The correction of the defective gene/protein represents the primary strategy for the treatment of these genetic conditions. However, the clinical translation of these approaches is very challenging because of the difficulty in achieving and maintaining therapeutic threshold levels of the corrective enzyme in targeted tissues (particularly in the brain) avoiding the toxicity associated to the high dosage of either viral vectors or infused corrective enzymes. To address this challenge, I have employed a strategy by which lysosomal enzymes are modified to improve their therapeutic potential. Specifically, I have developed and validated a tool through which is possible to generate gain-of-function variants of lysosomal enzymes that exhibit enhanced catalytic activity and/or increased stability in physiological conditions. I believe that enzyme variants generated by my work may produce a beneficial effect in targeted tissues (particularly in the brain) more efficiently and therefore, at lower doses compared to the respective WT enzymes. Therefore, my data may pave the way for the development of enhanced replacement therapies with improved clinical translationability to treat CNS in multiple LSDs.