Lysosomal-Targeted Strategies for TBCK Syndrome
Awardee: Xilma Ortiz-Gonzalez
Institution: University of Pennsylvania
Grant Amount: $40,000.00
Funding Period: February 1, 2023 - January 31, 2024
Summary:
We have recently co-discovered TBCK-encephaloneuronopathy (TBCKE) syndrome. Many of the patients that helped us establish the genetic link to the disease are my patients in the CHOP neurogenetics clinic. Using patients’ cells, we first reported that TBCK mutations alter autophagy, and then showed that there is secondary mitochondrial dysfunction (ie cellular energy production) in patient cells. We suspect the abnormal mitochondria are due to dysfunctional recycling within the cell, which ultimately happens in the lysosome. Our data suggests that targeting the lysosome (by promoting acidification) can rescue the mitochondrial deficits in TBCK cells. We now propose to further investigate the basis of the lysosomal dysfunction as a potential therapeutic target for TBCK syndrome. We specifically will test 2 strategies that have clinically available (or soon to be available) drugs, to expedite the translation of our preclinical research to future potential clinical trials.