Eric Sorscher, M.D.
Children's Healthcare of Atlanta
Recent years have brought a historic development for some people suffering from cystic fibrosis (CF): the first FDA-approved drugs to treat underlying causes of this disease in its most common forms.
The new medicines, lumacaftor and ivacaftor, help about three out of every 10 individuals with CF in the United States, but a majority of patients are still in need. Eric Sorscher is searching for ways to expand treatment options for additional patients.
Sorscher joined Emory University in 2015 from the University of Alabama at Birmingham, where he directed the Cystic Fibrosis Center. His current research centers on a promising new pathway: a supplemental drug to improve the effectiveness of existing compounds for people with less common forms of CF.
Cystic fibrosis is a hereditary disorder caused by malfunctions in a protein called the "cystic fibrosis transmembrane conductance regulator," or CFTR. Normally, CFTR is a chain of approximately 1,500 amino acids creating a channel across the cell membrane. This channel transports ions from inside to outside the cells of major organs; the salt movement draws moisture and brings other effects, which wash away mucus and expel impurities like bacteria.
But in a cystic fibrosis patient, the CFTR channel is improperly constructed. Ions and moisture cannot travel across the cell membrane, so bacteria-laden mucus continues to build up around cells, eventually clogging a patient's lungs and digestive organs. This leads to symptoms such as chronic cough, trouble breathing, malnutrition, frequent lung infections and eventually, respiratory failure.
There are at least 1,900 different genetic mutations that can cause the CFTR channel to malfunction. In some patients, the CFTR channel construction is incomplete; in others, it doesn’t open or the amino acids are woven incorrectly. Thus, a drug that helps one patient may not help another. A major part of Sorscher’s research is devoted to better understanding the particular mechanism that fails in each of these scenarios, and by extension, which types of drug therapy might be needed to arrive at a successful treatment.
Sorscher also works with the most common genetic mutation, F508del. In this form of the disease, just one amino acid in the chain of 1,500 is missing — phenylalanine (F), at position 508. Though improperly produced, the channel still has some functionality. But the cell’s built-in quality control mechanisms destroy the mutant channel soon after it is generated, which is unfortunate, as a limited channel is better than none at all.
The recently approved CF drug Orkambi improves the channel's ability to fold properly. But Sorscher wants to increase the number of channels – the pool of CFTR available for folding correction – to increase the benefit of emerging pharmacotherapies. He and his colleagues are investigating the “quality control” process, attempting to determine how the cell identifies and deletes a misfolded CFTR.
For this project, they're turning to an unlikely source: yeast. Sorscher works with Dr. John Hartman and other collaborators at UAB to knock out individual yeast genes in rapid succession, testing each knockout specimen to see whether the genetic modification affects the quality control process in the cell. If they can pinpoint the genes that direct this process, they hope to identify targeted small-molecules that selectively rescue F508del.
In his new position at Emory University, Sorscher will have additional support from The Chemical Biology Discovery Center. He and his colleagues will use high-throughput, cell-based drug screening techniques — a rapid, computing-driven way to analyze a large number of drug compounds in less time.
Sorscher and his team were also the first to conduct clinical trials using a non-viral vector for gene transfer of functional CFTR in cystic fibrosis treatment. Since the move to Emory, they plan to continue that research in collaboration with colleagues at Georgia Tech.
Along with his work in cystic fibrosis, Sorscher is a key contributor to research in gene-therapy technology for combating cancer. While at the University of Alabama at Birmingham, Sorscher collaborated with Dr. William Parker, then a senior scientist at Southern Research Institute, to develop a novel therapeutic treatment for solid tumors. This therapy uses a patented enzyme, E. coli purine nucleoside phosphorylase, to produce targeted, potent chemotherapy within the tumor cells themselves.
The technology is now licensed by biopharmaceutical company PNP Therapeutics®, Inc. As one of the founding scientists, Sorscher continues to serve on the company’s scientific advisory board, overseeing its ongoing clinical trials and research.
Straight from the Scholar
The environment at Emory is outstanding, and my scientific colleagues are spectacular. Thanks to the resources and support from Georgia Research Alliance, we can contribute to the research community in Atlanta, as well as nationally and internationally.