Description
Cystic fibrosis (also known as CF) is a common hereditary disease which affects the entire body, causing progressive disability and often early death. The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s. Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated, though not cured, by antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and infertility result from the effects of CF on other parts of the body.
CFTR are proteins anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and other affected organs. They are small channels for Cl to pass through. In the case of CF where CFTR protein does not work properly, salt and water will not be secreted to the lumen of the lungs properly, resulting in more viscous, nutrient-rich mucus in the lungs that allows bacteria to grow, and therefore frequent lung infections.
CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein. This mutation (F508-del-CFTR) accounts for 70% of CF cases worldwide and 90% of cases in the United States.
Flatley Discovery Lab focuses on discovering small molecules that modulate the function of CFTR protein, known as CFTR modulators that help to restore CFTR normal functions. To realize this goal, Flatley Discovery Lab uses cell-based CFTR functional screening technologies. A high throughput screening (HTS) platform has been established in the lab. Flatley Discovery Lab is also seeking more advanced hit validation assays with model cells that more closely resemble the epithelia cells from the lungs of CF patients. With these capabilities, Flatley Discovery Lab will become a productive CF drug discovery group, and will be able to produce more high quality drug candidates for clinical development.
Key research and discovery activities:
- High throughput screening of large diverse compound libraries
- Electrophysiology for lead validation support
- Improvement of CF assays and screening
Key R&D capabilities:
- Mammalian cell culture, including primary HBE cells
- Cell-based CFTR functional assay (Ussing chamber assay) for lead validation and optimization
- Cell-based high throughput screening (HTS) CFTR functional assay (384-well format) for large scale chemical library screening
- Protein chemistry assays for CFTR protein expression, trafficking, and drug mechanism studies
- DNA and RNA assays for CFTR expression and drug mechanism studies
- Molecular level electrophysiology assays (patch-clamp) for CFTR gating modulation and drug mechanism studies
