Pharmacological suppression of nonsense mutations to treat genetic diseases

Abstract

We are exploring the use of pharmacological agents to suppress nonsense mutations that cause genetic diseases. This approach could theoretically restore the synthesis of full length, functional proteins and relieve disease phenotypes. Much of our work focuses on cystic fibrosis (CF), a life‐threatening genetic disease that compromises function of the lungs and pancreas. CF is caused by mutations in the CFTR gene, which encodes the CFTR protein, a cAMP‐activated chloride channel. In cultured cells, we have shown that readthrough agents such as gentamicin and ataluren (formerly PTC124®) suppress CFTR nonsense mutations, resulting in a partial restoration of CFTR protein and function. Using a transgenic mouse model expressing the human CFTR gene with the G542X nonsense mutation found in CF patients, we have shown that these compounds can restore human CFTR expression and function in vivo. Recent data from a phase II clinical study support these conclusions, and show that ataluren can reduce the electrophysiological defects associated with CFTR nonsense mutations in CF patients. This therapeutic approach is also currently being applied to Duchenne Muscular Dystrophy and the lysosomal storage disease Hurler syndrome (MPS I‐H). Together, these results suggest that this approach could benefit a genotypic subset of patients with a wide range of genetic diseases caused by nonsense mutations. Supported by NIH RO1 NS057412 and P30 DK072482.