Ribosomal Nonsense Mutation Read-Through

The ability of certain compounds to induce ribosomal nonsense mutation “read-through", is well known. We have isolated new compounds that exhibit “read-through” activity using a unique screening method developed in our lab.

We have also discovered conditions that enhance “read-through” levels and are currently investigating these mechanisms.

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The establishment of a stable cell line system for nonsense mutation read-through compounds screen.

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Serum starvation increases read-through activity.

Importantly, we have translated our pre-clinical data on nonsense mutation “read-through” into a successful clinical trial. In collaboration with Prof. Revital Kariv from the Sourasky Medical Center, Familial Adenomatous Polyposis (FAP) patients were treated with a macrolide antibiotic we identified as a “read-through” enhancing agent, to restore the expression of the APC protein.

FAP is an inherited CRC syndrome caused by an APC germline mutation which leads to a secondary APC somatic mutation and APC loss of function. In our clinical trial FAP patients with identified APC nonsense mutations were treated with Erythromycin and most patients showed reduced polyp burden and decreased cellular tumorigenesis.

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A decrease in cell proliferation (KI67 staining) and active β-catenin expression following 4 months of Erythromycin treatment.

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Clinical trial results: decrease in adenoma size and number.