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Publication Date

5-2022

Abstract

Vici Syndrome is a devastating genetic pediatric disorder with complex clinical phenotypes. Affected children exhibit profound developmental delay, seizures, hypotonia, immunodeficiency, cardiomyopathy, and progressive loss of motor function, with a median survival of 42 months. This recessive genetic disorder is caused by deleterious variants in the EPG5 locus. This gene encodes a critical component of the intracellular machinery which couples autophagocytic material to the lysosome for degradation. In the absence of EPG5 function, autophagy is impaired, resulting in selective and progressive neuronal and other cellular damage leading the complex phenotypes of Vici Syndrome. VS is thus a member of an expanding class of diseases, termed congenital disorders of autophagy, in which deficits in autophagy are believed to be the underlying driver of the disease. There are essentially no treatment options for children with Vici Syndrome.

Therapies are desperately needed to enhance and extend the quality of life of these children. The overarching long term goals of this project are to identify small molecules that enhance autophagy for use in treatment of this devastating disorder, in a precision therapeutic effort. In this study we are taking a transdisciplinary approach to identify and validate novel therapies for Vici Syndrome. Our team has generated novel cell and animal models in an effort to recapitulate the relevant molecular, cellular, and whole animal aspects of the disease.

VS patient-specific induced pluripotent stem (iPS) cells from two VS patients and an unaffected sibling have been reprogrammed in our lab. Each of these lines were engineered to carry a reporter for autophagy amenable for high throughput screening and analysis of autophagocytic defects. A initial high throughput screen of FDA approved compounds was performed on undifferentiated iPS cells. Our initial efforts have identified several compounds that enhance autophagy and warrant further study. Further screens will be performed on cardiomyocytes and neurons differentiated from the engineered iPS cells.

In a parallel effort, two novel mouse models of Vici Syndrome have been recently engineered using genome editing to recapitulate two clinically identified deleterious variants of EPG5. Future studies in these models will include assessment of viability and deficits in autophagy, to confirm their utility as a disease model and to define the baseline of phenotypes. We will also initiate testing of the drug hits that have come out of our drug screening efforts.

Document Type

Poster

A Screen For Therapies For Vici Syndrome, A Rare Neurodegenerative Disorder Of Autophagy

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