Ribosomal Nonsense Mutation Read-Through
Nonsense Mutation Suppression
The ability of certain compounds to induce ribosomal nonsense mutation suppression (readthrough), is well known. We have isolated new compounds that exhibit readthrough activity using a unique screening method developed in our lab.
We have also discovered conditions that enhance antibiotic-mediated readthrough demonstrating a tight relation between the protein translation process and nonsense suppression efficacy.
Nonsense suppression results in the production of truncated mostly non-functional proteins (A). Readtheough agents can overcome this premature termination (B). Targeting different stages in the protein translation machinery enhances antibiotic mediated readthrough (C-D).
Importantly, we have translated our pre-clinical data on nonsense mutation readthrough into a successful clinical trial. In collaboration with Prof. Revital Kariv from the Sourasky Medical Center, Familial Adenomatous Polyposis (FAP) patients were treated with erythromycin to restore the expression of the APC protein.
FAP is an inherited CRC syndrome caused by an APC germline mutation, leading to a secondary APC somatic mutation and APC loss of function. In our clinical trial, seven out of the ten patients responded with maintained decreased polyp burden and decreased cellular tumorigenesis.
FAP clinical trial results: Decrease in adenoma size and number (A).
Decrease in cell proliferation (KI67 staining) after 4 months of Erythromycin treatment (B).