Therapeutic Targets for TPI Deficiency

Triosephosphate isomerase (TPI) deficiency is a rare, recessive metabolic disorder that causes hemolytic anemia, locomotor impairment, increased susceptibility to infection, progressive neurodegeneration, and muscle weakness that can affect lung and heart function. Anemia due to TPI deficiency begins in infancy, and individuals with this condition rarely survive past childhood. Research suggests that mutations resulting in reduced TPI protein stability underlie disease pathogenesis. Accelerated protein turnover is a common mechanism of disease pathogenesis, and very few good targets exist for stabilizing cytosolic proteins. Although TPI deficiency is a very rare disease- around 40 cases are documented in medical literature- a treatment for it could also work for countless other biomedically important diseases with similar disease pathogenesis.

Description

In order to identify novel factors that modulate mutant TPI turnover, University of Pittsburgh researchers performed a genome-wide RNAi screen targeting known and predicted quality control proteins. Of more than 400 proteins screened, 25 regulators of TPI were identified, ten of which were novel and previously undescribed. These ten proteins are also conserved in mice and humans, making them more likely to be effective drug targets than other more promiscuous proteins. The proteins identified by this study may reveal novel pathways and drug targets to block degradation of functional, cytosolic proteins, and represent important therapeutic targets for drug development for TPI deficiency and other devastating diseases.

Applications

· Developing therapies for disease related to cytosolic protein turnover

Advantages

· Several of the identified proteins regulators are novel
· Conserved proteins are more likely to make effective drug targets

Invention Readiness

In vivo data

IP Status

https://patents.google.com/patent/US20240050440A1

Related Publication(s)

Hrizo, S. L., Eicher, S. L., Myers, T. D., McGrath, I., Wodrich, A. P. K., Venkatesh, H., Manjooran, D., Swoger, S., Gagnon, K., Bruskin, M., Lebedev, M. V., Zheng, S., Vitantonio, A., Kim, S., Lamb, Z. J., Vogt, A., Ruzhnikov, M. R. Z., & Palladino, M. J. (2021). Identification of protein quality control regulators using a Drosophila model of TPI deficiency. Neurobiology of Disease, 152, 105299. https://doi.org/10.1016/j.nbd.2021.105299

Vogt, A., Eicher, S. L., Myers, T. D., Hrizo, S. L., Vollmer, L. L., Meyer, E. M., & Palladino, M. J. (2021). A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency. SLAS Discovery, 26(8), 1029–1039. https://doi.org/10.1177/24725552211018198