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New Research on Mutant Protein, Responsible for Most Cases of Cystic Fibrosis, Could Pave Way for Treatment

 San Diego scientists’ work on a mutant protein responsible for most cases of cystic fibrosis may pave the way to treating the root cause of cystic fibrosis.

Scripps Research Institute (TSRI) scientists working with the mutant protein – called cystic fibrosis transmembrane conductance regulator (CFTR) -- discovered the protein frequently “talks” to the wrong cellular neighbors.

The protein becomes so busy talking to the wrong neighbors, it stops functioning normally and is prematurely degraded. In most patients with the mutated CFTR gene, called ΔF508, the gene that encodes the protein stops it from folding correctly. In turn, the protein is not processed correctly in cells.

“The proteins and the interactions we’ve identified really fuel the pipeline for new drug targets to treat cystic fibrosis,” said Casimir Bamberger in a statement. Bamberger is a research associate in the lab of TSRI Professor John R. Yates and co-first author of the new study with TSRI Staff Scientist Sandra Pankow.

People diagnosed with the disease suffer from persistent infections and mucus build-up in their lungs. Antibiotics can treat the infections resulting from the disease, but there is no treatment to date to fully restore lung function.

In their study, researchers built upon previous studies showing the mutant gene regains its function at low temperatures.

Freezing people is not a practical treatment, of course, but this showed us mutant CFTR can be functional,” said Pankow in a statement. “So the idea behind our new study was to find new drug candidates that could mimic what we see at low temperatures.”

Co-Purifying Protein Identification Technology (CoPIT) helped scientists analyze cell samples and identify the proteins CFTR interacted with.

In studying the mutant protein, they found that it created an entirely new “disease-specific” interaction network. For comparison, most mutant proteins only lack one or two crucial interactions, researchers said.

“Three hundred proteins changed their level of interaction, and an additional 200 proteins interacted with the mutated CFTR,” said Pankow in a statement. “It’s like the wrong people are talking to the mutated CFTR all the time.”

TSRI scientists narrowed the “disease-specific” interactions to eight key proteins that disrupted the mutant protein and used a gene silencing technique to block the mutant protein’s interactions with them. By doing so, they found the CTFR returned to partially normal functions.

Next, scientists will search for small molecule drug candidates that can target those eight disruptive proteins, in hopes of finding a treatment.

The CoPIT data has been publicly released by TSRI researchers so others can look into clinical implications.

Diego Calzolari, Salvador Martínez-Bartolomé, Mathieu Lavallée-Adam and William E. Balch of TSRI also worked on the study.

The study was published in the Nov. 30, 2015 issue of Nature.

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