Ataluren-promoted Therapeutic Nonsense Suppression for Neurofibromatosis

Nonsense codons are words in the genetic code that instruct the gene expression apparatus to stop the process of protein synthesis at a precise point, i.e., they delineate the boundary of the information in a gene that encodes a specific protein. Although nonsense codons are normally an integral part of the flow of information from DNA to RNA to protein, they also arise in random places within genes as a consequence of a specific type of mutation known as a nonsense mutation. Such mutations halt the process of protein synthesis prematurely and thus inactivate the function of genes and cause genetic disorders. Nonsense mutations comprise ~20% of the disease-causing mutations in neurofibromatosis type 1 (NF1).

The drug, ataluren, can suppress protein synthesis termination at premature nonsense codons and produce limited but functionally significant quantities of essential proteins in patients with Duchenne muscular dystrophy (DMD) and in mouse and tissue culture models of multiple diseases. In the experiments of this project, we will grow mouse cells and live mice whose NF1 genes harbor nonsense mutations and test whether ataluren can restore the synthesis and function of the NF1 protein in these cells and animals. Success with these experiments will lead us to initiate phase 2 proof-of-concept clinical trials with neurofibromatosis patients whose disease is caused by nonsense mutations.