Discovery of Compounds Promoting MECP2 Read-Through
Andrew Napper, PhD | Nemours/A.I. duPont Hospital for Children
Many of the most severely afflicted children with Rett Syndrome have nonsense mutations in the gene for the protein MeCP2. Genes provide a precise instruction code that directs cells to make proteins. Mutations are changes in the genetic code that often result in the production of protein that cannot function normally. Nonsense mutations are like a period in the middle of a long sentence, together with deletion of the words that should have followed. Nonsense mutations in the gene for MeCP2 introduce a “stop codon” prematurely, so that the code for MeCP2 is not read through to the end, and an entire portion of the protein is missing. A potential approach to reverse the effects of a premature stop codon is to discover drugs that “read-through” the stop signal and allow completion of intact MeCP2.
These “stop-codon” mutations are also found in a number of other genetic disorders such as Cystic Fibrosis and Duchenne Muscular Dystrophy. Pharmaceutical companies have invested considerable efforts to develop compounds that promote read-through, however, despite considerable effort, none of the read-through compounds developed to date have been able to reverse the pathology of Rett syndrome.
Dr. Napper employed an innovative drug discovery platform to identify novel drugs that could specifically promote read-through for Rett nonsense mutations but was not able to identify any compounds.
In reviewing the research landscape, these compounds have shown little to no efficacy in human trials for other diseases including cystic fibrosis and Duchenne Muscular Dystrophy. Considering the lack of convincing preclinical efficacy in Rett Syndrome and the lack of efficacy of this class of compounds in other genetic disorders, we have decided to terminate this project.