As vice president for research affairs, William R. Skach, M.D., guides basic research efforts, drug discovery and preclinical therapeutic development programs for the Cystic Fibrosis Foundation.
He was previously professor in the Department of Biochemistry and Molecular Biology at Oregon Health & Science University, where he continues to run a research lab studying fundamental aspects of CFTR, the key protein in cystic fibrosis.
Dr. Skach recently discussed the latest advances in CF research and exciting new approaches to address the underlying cause of the disease.
Can you tell us about the progress of therapies targeting the defective CFTR protein in CF?
On July 2, the FDA approved the lumacaftor/ivacaftor combination drug (Orkambi™) for people with CF ages 12 and older with two copies of the F508del mutation. This represents about one-third of the CF population in the United States. Nearly half of individuals with CF have two copies of this mutation and could eventually benefit from the therapy.
The Foundation is supporting the discovery and development of more therapies that modulate the defective CFTR protein in people with CF. Vertex is conducting several clinical trials of ivacaftor combined with another potential drug, VX-661, in people with either one or two copies of F508del.
A number of other leading pharmaceutical companies are investigating small molecule compounds that could similarly correct the misfolded CFTR protein caused by the F508del mutation. In April, Cystic Fibrosis Foundation Therapeutics Inc. (CFFT), the nonprofit affiliate of the Cystic Fibrosis Foundation, announced a $14 million expansion of its research agreement with Genzyme to promote development of new treatments for people with F508del.
What progress have we made in treating rare mutations of CF?
There is now a large, coordinated effort to develop treatments for people with CF mutations other than F508del.
One major ongoing initiative, called CFTR2, is focused on defining the genetics and clinical characteristics of different CF mutations, including rare mutations that we know very little about. The project is overseen by Dr. Christopher Penland at the Foundation and led by a team at Johns Hopkins University, aided by collaborators in Canada and Italy.
CFTR2 has gathered information on nearly 40,000 people with CF from around the world and has so far described the characteristics of about 160 mutations.
Could you tell us about other promising approaches to treating the basic defect?
Some exciting new strategies in the early stages target groups of mutations, including those known as nonsense and splicing mutations, by addressing earlier cellular processes that generate the protein.
One example is RNA therapy, in which CFTR messenger RNA is either added directly to cells for production of a normal CFTR protein or the defective messenger RNA is repaired in the cell. A research project is currently underway with the biopharmaceutical company Shire plc to investigate a novel technique of delivering normal messenger RNA directly to the lungs of a person with CF.
Another strategy, called gene editing, takes advantage of emerging technology that is capable of repairing the faulty gene itself.
The Foundation is exploring gene editing and stem cell research. While much has been learned about peripheral stem cells in recent years, it is not yet clear exactly how they can be used in the lungs. First, we need to identify critical stem cell populations in the airways, understand how they behave and then develop ways to correct the CFTR gene. Thus, stem cell research must go hand in hand with work on gene editing.
Because they are so new, these strategies will likely take time to develop. Efforts in these areas are therefore being expanded alongside the next generation of CFTR modulators to bring them to people with CF as soon as possible.