Corrective Treatment for CTNNB1 Syndrome

National Center For Advancing Translational Sciences

Investigators

Abstract

The medicinal chemistry team has established a lead optimization plan and defined milestones for the project. So far, the team has synthesized more than 200 potential GSK3 inhibitors for potency and DMPK evaluation. The biology group has established enzymatic and cellular assays for screening the compounds selected by the medicinal chemistry group to determine the enzymatic function and cellular responses for selecting candidate compounds. The DMPK group conducted Tier I and Tier II absorption, distribution, metabolism and excretion (ADME) assays to determine the solubility, permeability, and brain penetration ability of the candidate compounds. They also started metabolite identification studies and pharmacokinetics (PK) studies for the lead compounds to determine metabolic stability and the PK profile. The biology lab also worked with the collaborator (Tufts) to obtain induced pluripotent stem cells (iPSCs) from six patients (representing 6 different pathologic mutations). The patient iPSCs were then subjected to CRISPR/Cas9-mediated gene correction, to generate revertant lines to act as matched healthy controls for each patient line. The mutant and revertant iPSCs are being used to test the ability of the current lead GSK3 inhibitor compounds to restore beta-catenin levels. As additional GSK3 inhibitors are identified by the medicinal chemistry team, these will also be tested in the iPSC system.