The Southern Research Therapeutic Program for Cystic Fibrosis

Southern Research announced a $7.5 million award from the Cystic Fibrosis Foundation Therapeutics (CFFT) — the nonprofit drug discovery affiliation of the Cystic Fibrosis Foundation (CFF) — to support the development of novel therapies for people with cystic fibrosis with rare genetic or “nonsense” mutations.

Researchers at the University of Alabama at Birmingham (UAB), who have been collaborating with Southern Research through the Alabama Drug Discovery Alliance (ADDA), also are part of the drug development partnership. The announcement came in October 2015.

About CF and nonsense mutations

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a channel that regulates the transport of chloride ions in and out of cells. This ion transport is crucial to water movement in tissues and is essentially linked to the production of thin mucus that protects and lubricates the lungs, pancreas and other organs, entire systems such as digestion, or body tissues.

CF is a genetic disease caused when a mutation occurs in the CFTR gene, which encodes for the CFTR protein. Different kinds of mutations are found in cystic fibrosis. Some affect the opening of the CFTR channel (G551D), while others cause messenger RNA (mRNA) to transmit a stop signal. These are called nonsense mutations, in which the premature stop signal results in a shortened and nonfunctional CFTR protein.

The defective protein affects the transport of chloride ion and water movement in tissues, resulting in the production of a thick mucus that accumulates in vital organs. This is a favorable environmental for bacterial growth, leading to repeat infections and inflammation that can become life threatening for people with CF.

Southern Research therapeutic approach for CF

Using special tests developed by UAB, Southern Research’s is working to identify compounds through a screening process in its chemical library. These compounds are aimed at targeting the premature stop signals which cause the defective CFTR protein.

Some of the research results were recently published in a study titled “Discovery of clinically approved agents that promote suppression of CFTR nonsense mutations.” The study used two independent screens (firefly luciferase and a CFTR-mediated transepithelial chloride conductance assay) on a library of clinically available compounds using fisher rat thyroid cells modified with stop codons. Some of these compounds were further evaluated for other screening assays that used cells from CF patients. The effect of the FDA-approved drug Kalydeco (ivacaftor) was also tested in combination with the most effective compounds.

Results showed that clinically approved compounds identified as potential read-through agents, in combination with ivacaftor, may induce nonsense suppression and restore CFTR function. The research team also reported that one or more compounds may be suitable to advance to clinical study.

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