Developing a murine TPI Df model

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Abstract/Project summary: TPI Df is a devastating untreatable childhood metabolic disease resulting in anemia, paralysis, irreversible brain damage and premature death. Numerous subtle amino acid substitutions in Triosephosphate Isomerase (TPI) are pathogenic and result in rapidly progressing multisystem disease. Importantly, pathogenic TPI Df mutations have been shown to result in protein that retains function but are unstable. Pathogenesis of numerous TPI DF mutations is known to result from increased turnover of the functioning protein by Protein Quality Control pathways (PQC). We have developed a human cellular TPI Df model of the “common” mutation and validated its use in optical screening. We are utilizing this model in an automated compound screening platform to identify first in class TPI Df small molecule therapies. To validate small molecule therapies there is a desperate need for a mammalian model of TPI Df. This proposed research will meet this need by using CRISPR to create a TPI Df model with the “common” mutation. A mouse model with construct validity for TPI Df that demonstrates analogous behavioral, physiological, and metabolic phenotypes is an important resource for the research community.