January, 12, 2016- PBA announces the award of a $325,000 Phase I STTR grant from the National Heart, Lung, and Blood Institute (NHLBI). The project, entitled, “Human nasal epithelial organoids as a non-invasive, personalized model for predicting effectiveness of CFTR modulators in cystic fibrosis patients,” lays the groundwork for personalized screening of CFTR-modulating drugs with the ultimate goal of identify effective drugs for the treatment of cystic fibrosis. The proposed research will be conducted via a collaboration between PBA and the Gentzsch Lab at the University of North Carolina at Chapel Hill.

 

About the Project:

The discovery of the single gene (CFTR) that causes cystic fibrosis (CF) has been transformational, focusing treatment on modulator drugs that restore function of the CFTR gene product. CFTR “correctors” enhance transport of mutant protein to the cell membrane and CFTR “potentiators” activate mutant protein that does get to the membrane. The FDA-approved potentiator drug ivacaftor (Kalydeco) has resulted in remarkable quality of life improvements for the ~5% of the CF population with specific, responsive CFTR mutations. Mixed results, but none approaching the ivacaftor outcome, have been achieved for the remaining majority of the CF population. The major hurdle is that over 2,000 different CFTR gene mutations have been identified, some relatively frequent and others quite rare, so that available cell-based assays for testing potential drugs have unpredictable relevance for an individual with CF. In the absence of cell-based ex vivo or any known in vivo assays, there are no reliable predictors of clinical outcomes specific to the individual, leading to arduous, potentially harmful, trial and error drug treatment without any predictive basis for success. This project seeks to overcome this hurdle by developing a personalized, ex vivo, minimally invasive, and predictive screening assay for CFTR modulator activity. Cells from a single, minimally invasive nasal biopsy are cultured to generate many organoids, three-dimensional cultures that remarkably and relatively quickly replicate the nasal epithelium, exhibiting cilia and producing mucus. Each organoid constitutes an ex vivo replica of the donor’s nasal cells, amenable to drug testing, detailed probing of outcome measures and precise measurement of restored CFTR activity. The ability to generate many organoids from a single biopsy allows combinatorial drug testing of restored CFTR activity for that person, and the potential to optimize all available drugs for an individual.

 

About Cystic Fibrosis:

Cystic fibrosis (CF) is a rare, life-shortening genetic disease affecting approximately 30,000 in the United States and 75,000 people world-wide. CF is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes — one from each parent — to have CF. There are approximately 2,000 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working or too few CFTR proteins at the cell surface. The defective function or absence of CFTR protein results in poor flow of salt and water into and out of the cell in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the mid-to-late 20s.

 

About STTR Grants:

The Small Business Technology Transfer (STTR) is another program that expands funding opportunities in the federal innovation research and development (R&D) arena. Central to the program is expansion of the public/private sector partnership to include the joint venture opportunities for small businesses and nonprofit research institutions. The unique feature of the STTR program is the requirement for the small business to formally collaborate with a research institution in Phase I and Phase II. STTR’s most important role is to bridge the gap between performance of basic science and commercialization of resulting innovations. Additional information may be found on the Small Business Administration webpage.