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AssigneeUniversity of Pittsburgh—Of the Commonwealth System of Higher Education
InventorsMichael John Palladino, Stacy Lynn Hrizo, Andreas Vogt
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Triosephosphate isomerase deficiency (TPI Df) is a devastating childhood degenerative disease for which there are currently no treatments. Pathogenesis of this disease is driven by mutations that destabilize the TPI protein. A genome-wide RNAi screen in Drosophila to identify regulators of TPI stability is described. The screen identified 25 proteins that are critical to TPI stability, each of which has a human ortholog. Methods of promoting TPI protein stability and treating TPI Df in a subject by administering a therapeutically effective amount of an agent that inhibits expression or activity of one of the identified regulators are described. Also described is a method for the identification of agents capable of promoting stability of mutant TPI. Methods for treating a subject who has TPI Df by administering an agent that promotes stability of mutant TPI is also described.
A method for identifying an agent that promotes stability of a mutant form of the human triosephosphate isomerase (TPI) protein, comprising:
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A method of treating a subject who has triosephosphate isomerase deficiency (TPI DO, comprising administering to the subject a therapeutically effective amount of an agent that promotes stability of a mutant form of the human TPI protein.
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A method of treating triosephosphate isomerase deficiency (TPI Df) in a subject, comprising administering to the subject a therapeutically effective amount of an agent that inhibits expression or activity of aconitase 1 (ACO1), actin related protein 3 (ACTR3), anaphase promoting complex subunit 10 (ANAPC10), anti-silencing function 1A histone chaperone (ASF1A), cell division cycle 34, ubiquitin conjugating enzyme (CDC34), carboxypeptidase B1 (CPB1), crystallin alpha A (CRYAA), cullin 3 (CUL3), dynein axonemal assembly factor 4 (DNAAF4), DnaJ heat shock protein family (Hsp40) member B11 (DNAJB11), DnaJ heat shock protein family (Hsp40) member C2 (DNAJC2), DnaJ heat shock protein family (Hsp40) member C15 (DNAJC15), endoplasmic reticulum protein 29 (ERP29), GTP binding protein 6 (GTPBP6), heat shock protein family B (small) member 1 (HSPB1), HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1), MPV17 mitochondrial inner membrane protein like 2 (MPV17L2), proteasome 20S subunit alpha 7 (PSMA7), SEC61 translocon subunit gamma (SEC61G), translocase of outer mitochondrial membrane 22 (TOMM22), ubiquitin conjugating enzyme E2 B (UBE2B), ubiquitin conjugating enzyme E2 Q1 (UBE2Q1), ubiquitin specific peptidase 14 (USP14), ubiquitin specific peptidase 16 (USP16), or ubiquitin specific peptidase 45 (USP45), thereby treating TPI Df in the subject.
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A method of promoting stability of a mutant form of the human triosephosphate isomerase (TPI) protein in human cells, comprising contacting the cells with an effective amount of an agent that inhibits expression or activity of aconitase 1 (ACO1), actin related protein 3 (ACTR3), anaphase promoting complex subunit 10 (ANAPC10), anti-silencing function 1A histone chaperone (ASF1A), cell division cycle 34, ubiquitin conjugating enzyme (CDC34), carboxypeptidase B1 (CPB1), crystallin alpha A (CRYAA), cullin 3 (CUL3), dynein axonemal assembly factor 4 (DNAAF4), DnaJ heat shock protein family (Hsp40) member B11 (DNAJB11), DnaJ heat shock protein family (Hsp40) member C2 (DNAJC2), DnaJ heat shock protein family (Hsp40) member C15 (DNAJC15), endoplasmic reticulum protein 29 (ERP29), GTP binding protein 6 (GTPBP6), heat shock protein family B (small) member 1 (HSPB1), HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1), MPV17L2, proteasome 20S subunit alpha 7 (PSMA7), SEC61 translocon subunit gamma (SEC61G), translocase of outer mitochondrial membrane 22 (TOMM22), ubiquitin conjugating enzyme E2 B (UBE2B), ubiquitin conjugating enzyme E2 Q1 (UBE2Q1), ubiquitin specific peptidase 14 (USP14), ubiquitin specific peptidase 16 (USP16), or ubiquitin specific peptidase 45 (USP45), thereby promoting stability of the mutant TPI protein.
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Dependencies are inferred from the claim text.