Exploring Nonsense Suppression as a Treatment for NF1

Nonsense mutations are gene lesions that introduce a premature termination codon (PTC) into a messenger RNA (mRNA). Since PTCs are found in a significant number of NF1 patients, we propose to identify therapies that suppress the effects of PTCs to restore neurofibromin protein expression and function. We developed and characterized reporters that can detect compounds capable of suppressing termination at PTCs and/or inhibiting nonsense-mediated mRNA decay (NMD) of PTC-containing mRNAs. A total of 771,345 small molecules were screened and 157 compounds were confirmed as hits. This project examines whether this collection of new, validated, PTC suppression agents restore full-length neurofibromin protein and its function in NF1 cell and animal models that carry nonsense mutations. The goal of this study is to identify multiple compounds for advancement to Investigational New Drug (IND) status in preparation for future clinical trials.

Investigators

David Bedwell, PhD 

University of Alabama, Birmingham

Bruce Korf, MD, PhD

University of Alabama, Birmingham

Mark Suto, PhD

Southern Research

David Bedwell, PhD 

University of Alabama, Birmingham

Bruce Korf, MD, PhD

University of Alabama, Birmingham

Mark Suto, PhD

Southern Research

Current Stage

Discovery

Discovery
In Vivo Proof of Concept
IND Enabling
Clinical Trial Phase 1
Clinical Trial Phase 2
Clinical Trial Phase 3