Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia and muscle weakness that quickly progresses with severe neuromuscular dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~ 5 years. Previous work by UPDDI collaborator Michael Palladino has shown that elevating mutant TPI levels by genetic or pharmacological intervention can ameliorate symptoms of TPI DF in fruit flies. To identify compounds that increase levels of mutant TPI, we have developed a stable cell line expressing the common TPI Df protein fused with green fluorescent protein (HEK [TPIE105D]-GFP), which was implemented for high throughput screening (HTS) and has yielded several potential candidates for treatment of this devastating childhood disease. We thank the National Institute of Child Health and Development for financial support and the brave patient and his parents who donated cells for research.
For a documentation of why this project is important please see this short video. https://www.savejt.com/gallery/video/
We thank the National Institute of Child Health and Development for financial support and the brave young patient and his parents who donated cells for research.
Hrizo SL, Eicher SL, Myers TD, McGrath I, Wodrich APK, Venkatesh H, Manjooran D, Swoger S, Gagnon K, Bruskin M, Lebedev MV, Zheng S, Vitantonio A, Kim S, Lamb ZJ, Vogt A, Ruzhnikov MRZ, Palladino MJ. Identification of protein quality control regulators using a Drosophila model of TPI deficiency. Neurobiol Dis. 2021;152:105299. PMID: 33600953; PMCID: PMC7993632. https://doi.org/10.1016/j.nbd.2021.105299
Vogt A., Eicher S., Myers T., Hrizo S., Vollmer L., A, Meyer EM., and Palladino MJ. A high content screening assay for small molecules that stabilize mutant triose phosphate isomerase (TPI) as treatments for TPI-deficiency. SLAS Discov. 2021 Jun24, Online ahead of print. PMID: 34167376; PMCID: NIHMS1704229. https://doi.org/10.1177/24725552211018198
Recently awarded grants
1. NIH R01 HD105311 “Developing the first TPI Df therapeutics”
2. NIH R01 HD104346 “High-content screening for TPI Deficiency therapeutics”