CF & Small Molecules

Crossing Boundaries for a Treatment

Cystic Fibrosis (CF) is a rare autosomal recessive genetic disorder caused by one of 2,000 possible mutations found in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The disorder results in excess mucus in the lungs and repeated infections that lead to progressive, irreversible lung damage that ultimately shortens the lifespan of the 30,000 individuals affected in the US. Most current treatments focus on alleviating symptoms of the disease and typically include antibiotics, thinning mucus, and chest physiotherapy, but there are few effective treatments that target the root cause of CF. Currently, there is one drug that targets and improves the function of the CFTR, but it only works for a small fraction of the overall population of CF patients. This leaves a large majority of those with CF without an effective treatment, and therefore there exists a high level of unmet need for the CF population. At Emory University, Nael McCarty, PhD, Professor of Pediatrics and his team have been studying the CFTR protein since 1990 and have recently developed new compounds that potentiate the function of the defective CFTR. This discovery is based upon recent technological advances in the work of the McCarty Lab and those developments have enabled his team to rapidly progress in understanding the mechanisms underlying CFTR function and dysfunction.

Human Lungs

The new compounds were identified after virtually screening a library of 7 million compounds – a large number compared to the 228,000 compounds analyzed in the process that identified the currently available drug. McCarty partnered with Israeli researcher Hanoch Senderowitz, PhD of Bar Ilan University, who initially screened the compound library through a pharmacophore modeling system. After potentially useful compounds were identified through the computational high throughput screening, the McCarty lab closely evaluated these compounds experimentally. The team is continuing to test and refine the design of potential compounds using an iterative process, which will allow continued improvement in the pharmacophore model used for virtual screening.

McCarty describes the CF drug development process as a partnership between academics and industry, “We need both groups to work together. The discovery process starts in academic labs, then develops in industry, then goes back to academics to be improved upon. We academicians can learn from the successes and failures of industry in order to develop even better drugs.” His new drug candidates exemplify the collaboration and mutually beneficial relationship between the two partners. Academic researchers help develop the basic mechanistic understanding, while industry researchers can engage in more specific development of treatments.

McCarty’s new potential small molecule treatments for CF build upon the currently available treatment strategies and open doors to potential treatments for several related disorders. CF is just the initial target for these small molecule compounds; they also may be beneficial for the treatment of COPD and secretory diarrhea, which are medical issues also related to the CFTR protein. Although CF is considered a rare disease, COPD is a chronic condition that affects millions in the U.S. alone and a treatment would have a widespread positive impact. Currently Emory is pursuing patent protection around the lead compounds and will soon begin additional validation and POC assessment. As these lead compounds develop further, the McCarty lab will also continue to screen additional compounds for CF and the other conditions related to CFTR. “We are very excited and enthusiastic about these new CFTR potentiators, and look forward to their continued development toward the clinic,” said Assistant Director of Licensing, Cliff Michaels.

Techids: 15086, 15087