Gruthan Bioscience, LLC, a Medical University of South Carolina startup based in Charleston, South Carolina, received a Small Business technology Transfer (STTR) award from the National Heart, Blood and Lung Institute in August to take the next step in developing a novel class of cholesterol-lowering drugs to treat familial hypercholesterolemia.
The startup was founded by liver researcher Stephen Duncan, Ph.D., SmartState Chair in Regenerative Medicine and chairman of the Department of Regenerative Medicine and Cell Biology at MUSC.
Patients with familial hypercholesterolemia have very high levels of low-density lipoprotein cholesterol (LDL-C), colloquially known as "bad cholesterol." The receptor that should bind to the cholesterol and remove it from the blood is mutated and no longer functions.
A subset of these patients inherit mutations in the LDL receptor from both parents and are at high risk of developing severe and deadly cardiovascular disease at a young age. Unfortunately, they do not respond to any of the four major classes of cholesterol-lowering drugs. According to Duncan, that's because most of those drugs act through the LDL receptor.
The most common drugs on the market, for example the statins, work by increasing the level of the LDL receptor on liver cells. Having more LDL receptors means the liver can clear more cholesterol and keep the level of cholesterol in the blood at normal levels. However, patients who have mutations in both copies of the LDL receptor gene don't respond well to statins because they lack a functioning LDL receptor. It's a typical catch-22: Statins work through the LDL receptor, but if your LDL receptor is broken, statins don't work."
Stephen Duncan, Ph.D., Liver Researcher and Chairman, Department of Regenerative Medicine and Cell Biology, MUSC
Duncan is also the SmartState Chair in Regenerative Medicine
While two new drugs have been approved for treating this life-threatening disease, these drugs can have serious side effects.
Gruthan Bioscience LLC aims to develop a new class of drugs for the safe and effective treatment of patients with this rare form of familial hypercholesterolemia. Duncan is passionate that it is up to academic investigators like him to help to develop drugs for rare diseases that are unlikely to promise the profit margin needed to attract a pharmaceutical company.
"The contributions of academic researchers to drug discovery is absolutely crucial for the study of rare diseases and the identification of potential treatments," said Duncan.
"Although rare diseases as a class are common, patients with a specific disease may number a few hundred worldwide."
"From a business perspective, such low numbers of patients make it difficult to justify the billions of dollars needed for the research and development that is required to generate new treatments. However, academics are not driven by a need to generate profits and can tackle problems using exploratory high-risk approaches, which sometimes lead to significant breakthroughs."
In this case, the novel class of drugs developed for a rare disease might also have applications for lowering cholesterol in the broader population.
"The focused goal of the work is to provide familial hypercholesterolemia patients with a safe treatment," said Duncan. "However, because the compounds we have found appear to represent a new class of cholesterol-lowering molecules, we believe that they serendipitously have the potential to be used broadly to help patients with high cholesterol meet their goals."
Duncan had to overcome a number of challenges to develop this new class of cholesterol-lowering drugs. First, it is difficult to test potential drugs for familial hypercholesterolemia in a cell-culture system that adequately mimics the deficiencies in liver function and cholesterol metabolism that are characteristic of the disease. Duncan has developed an innovative procedure for doing so.
"Around 12 years ago, my lab developed a procedure that allows us to make hepatocytes, or liver cells, from stem cells that shared many characteristics with normal liver cells," he explained.
"This provided a persistent source of hepatocytes from any patient with a genetic liver disease. By having access to such cells, we could reproduce the patient's liver disease in the laboratory and use the cells to discover new therapies."
Having identified a therapeutic target using this novel procedure, Duncan screened small molecules in the South Carolina Compound Collection (SC3) with the help of Patrick Woster, Ph.D., Endowed Chair in Medicinal Chemistry in the Department of Drug Discovery and Biomedical Sciences at MUSC.
Housed in the MUSC Drug Discovery Core, the SC3 comprisess 150,000 fully annotated drug-like molecules collected from industry and academic donations or produced in-house. Using this collection, Duncan was able to identify the class of small molecules that Gruthan Bioscience will develop with the STTR funding.
"The immediate goal of the STTR project is to determine whether this new class of cholesterol-lowering drugs we have discovered also work in animals," said Duncan.
If the drugs prove to be capable of doing so, Duncan will apply for phase 2 funding to continue to advance them toward the clinic.
Duncan also believes that the novel cell platform he has developed can help to identify drugs for other challenging diseases.
"While we recognize the many challenges ahead, we are confident that we will continue to develop novel therapies for the treatment of some of the most challenging disorders afflicting patients and are excited to be heading into this new phase," said Duncan.