Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery
Abstract
Our objective is to screen libraries of several thousand compounds, including clinically approved drugs, for their ability to suppress the in vivo phenotypes observed in worm and fish models expressing mutant human TDP-43 related to ALS and validating hits in a mouse model. Our hypothesis is that chemical modifiers of TDP-43 in vivo function will provide new therapeutic approaches to ALS. In year 1, our screen of 3,750 FDA-approved compounds identified 20 active compounds, most of which were neuroleptics with the most potent being pimozide. In year 2, the objective (Aim 3) was to have screened a total of 10k molecules. In addition to the 4k screened in year 1, we screened 2k molecules that are structurally related to the neuroleptics as well as novel molecules. Also, we screened 4k novel derivatives of pimozide and identified several dozen active compounds and reached our objective of a total of 10k molecules screened to date. Testing of pimozide in TDP-43 mice (and in a new collaboration, patients) began (Aim 6).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA599884
Entities
People
- Alexandre Parker
- Edor Kabashi
- Jean-Pierre Julien
- Pierre Drapeau
Organizations
- Université de Montréal