Modulators of TDP-43 Mediated Toxicity and Methods of Use Thereof for Identifying Agents Having Efficacy for the Treatment and Prevention of Proteinopathies
AssigneesNational Institutes of Health (NIH), U.S. Dept. of Health and Human Services (DHHS), NIH Division of Extramural Inventions and Technology Resources (DEITR)
InventorsAaron D. Gitler, Andrew Elden
Life of this patent
Estimating the term…
Abstract
Compositions and methods are disclosed for identifying agents useful for the treatment of proteinopathies.
Claims19
A method for treating or inhibiting development of a proteinopathy in a subject in need thereof, the method comprising administering
- i) an effective amount of a pharmaceutical composition comprising a therapeutic amount of an agent which inhibits expression or activity of at least one gene selected from the group consisting of DBR1, PCL6, SAKI, YCK2, MEC1, UBP7, RGA2, KEL1, DIP5, ROM2, VHS1, YHR131C, SLF1, HRP1, PBP1, KEM1, MSN5, SRO9, SFG1, MSA1, PIB2, SLG1, MTH1, CDC6, TSCI 1, SOLI, KIN3, PBP2, SETS, CCE1, SIW14, YDR067C, DOM34, MGD1, RPL16 or human homologs thereof, or
- ii) an agent which increases expression or activity of at least one gene selected from the group consisting of FMP48, VTS1, XRS2, HSP104, TISI 1, BFR1, ICS2, YKL171W, PGM1, ADY3, RIM15, CYC8, RDR1, TIF4631, MRPL39, FLD1, MSN2, PBL16B, NHX1 or human homologs thereof, said inhibition or increase being effective to reduce cytotoxicity and/or aberrant protein aggregation in said subject.
A method of inhibiting TDP-43 mediated cellular toxicity, the method comprising contacting a cell expressing a toxicity inducing amount TDP-43 or a functional C-terminal variant thereof with an effective amount of an agent that inhibits expression or activity of at least one gene selected from the group consisting of DBR1, PCL6, SAKI, YCK2, MEC1, UBP7, RGA2, KEL1, DIP5, ROM2, VHS1, YHR131C, SLF1, HRP1, PBP1, KEM1, MSN5, SRO9, SFG1, MSA1, PIB2, SLG1, MTH1, CDC6, TSCI 1, SOLI, KIN3, PBP2, SET3, CCE1, SIW14, YDR067C, DOM34, MGD1, RPL16 or human homologs thereof, or an agent that increases expression or activity of at least one gene selected from the group consisting of FMP48, VTS1, XRS2, HSP 104, TISl 1, BFR1, ICS2, YKL171W, PGM1, ADY3, RIM15, CYC8, RDR1, TIF4631, MRPL39, FLD1, MSN2, PBLl 6B, NHX1 and human homologs thereof.
A method for identifying agents which inhibit TDP-43 mediated cellular toxicity, comprising:
- a) providing a cell which expresses wild type TDP-43 or a C-terminal functional variant of thereof containing amino acids 188-414, said expression being associated with increased protein aggregation and cellular toxicity;
- b) contacting said cell with an effective amount of an agent which inhibits expression or activity of at least one gene selected from the group consisting of
- i) PCL6, SAKI, YCK2, MEC1, UBP7, RGA2, KEL1, DIP5, ROM2, VHS1, YHR131C, SLF1, HRP1, PBP1, KEM1, MSN5, SRO9, SFG1, MSA1, PIB2, SLG1, MTH1, CDC6, TSCI 1, SOLI, KIN3, PBP2, SET3, DBR1, CCE1, SIW14, YDR067C, DOM34, MGD1, RPL16 or human homologs thereof or
- ii) an agent which increases expression or activity of at least one gene selected from the group consisting of FMP48, VTS1, XRS2, HSP104, TISI 1, BFR1, ICS2, YKL171W, PGM1, ADY3, RIM15, CYC8, RDR1, TIF4631, MRPL39, FLD1, MSN2, PBL16B, NHX1 and human homologs thereof;
- and
- c) measuring cellular toxicity in the presence of said agent relative to a non-treated control, wherein a decrease in cellular toxicity identifies an agent which reduces TDP-43 mediated cellular toxicity.
8-11. (canceled)
(canceled)
16-17. (canceled)
A transgenic yeast cell comprising a genetic construct which, upon expression, produces TDP-43 protein or a functional C terminal variant thereof, said yeast cell further comprising a nucleic acid construct encoding a TDP-43 activity modulator, said modifier altering TDP-43 toxicity when over expressed, said modified being selected from the group of modifiers shown in Table 2.
23-24. (canceled)
Dependencies are inferred from the claim text.