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

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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.

Evaluating the Effects of Selected Small-Molecules on a Zebrafish Model of TBCK Syndrome

Awardee: Gerald B. Downes

Institution: University of Massachusetts Amherst

Grant Amount: $50,400

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

TBCK Syndrome is a rare, poorly understood, severe neurological disease. In 2016 multiple publications first reported that mutations in the TBCK gene result in a progressive loss of muscle tone, intellectual disability, characteristic facial features, drug resistant epilepsy, and a high incidence of childhood or adolescent mortality. Outside of managing symptoms, there are currently no treatments to slow the progression of the disease. Animal models are often a key step towards better understanding a disease and developing new therapeutics, however there are currently no published animal models of TBCK Syndrome. Zebrafish are a widely used disease model due to several advantageous features, which also make this an excellent system to evaluate or screen for new therapeutic drugs. My laboratory is establishing a zebrafish model of TBCK Syndrome, and we have already created multiple tbck mutant lines and identified a phenotype. Our goals here are to continue characterizing the effects of tbck mutation on the zebrafish nervous system and to evaluate whether any of three different small-molecules, already FDA approved or known to be safe for human consumption, decrease the severity of tbck-mutant phenotypes. The completion of this project will establish a foundation to use zebrafish for small-molecule screens and help determine whether any of these compounds should be further investigated as a treatment for TBCK Syndrome.

Platforms for the identification and validation of candidate small molecule treatments for TBCK Syndrome

Awardee: Jay Vivian

Institution: University of Kansas Medical Center

Award Amount: $50,600

Funding Period: February 1, 2021 - January 31, 2022