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