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," explained Duncan. "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."
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.
About the Medical University of South Carolina
Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the state's only integrated, academic health sciences center with a unique charge to serve the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and nearly 800 residents in six colleges: Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state's leader in obtaining biomedical research funds, in fiscal year 2019, MUSC set a new high, bringing in more than $284 million. For information on academic programs, visit musc.edu.
As the clinical health system of the Medical University of South Carolina, MUSC Health is dedicated to delivering the highest quality patient care available, while training generations of competent, compassionate health care providers to serve the people of South Carolina and beyond. Comprising some 1,600 beds, more than 100 outreach sites, the MUSC College of Medicine, the physicians' practice plan, and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals situated in Charleston, Chester, Florence, Lancaster and Marion counties. In 2019, for the fifth consecutive year, U.S. News & World Report named MUSC Health the No. 1 hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.
MUSC and its affiliates have collective annual budgets of $3.2 billion. The more than 17,000 MUSC team members include world-class faculty, physicians, specialty providers and scientists who deliver groundbreaking education, research, technology and patient care.
About the MUSC Foundation for Research Development
The MUSC Foundation for Research Development is responsible for evaluating all intellectual assets the enterprise owns and generates, extracting value and forging industry and other relationships, resulting in products and services that provide real-life solutions to the world's medical needs. Whether our translations involve a technology license, research collaboration or new startup venture, we serve as a dedicated one-stop shop for advancing innovation at MUSC. Our team is also dedicated to building an ecosystem of innovation the activities of which contribute to MUSC's overall economic impact on our state and country. Please visit us online at http://www.
About the MUSC Department of Regenerative Medicine and Cell Biology
The goal of the department is to apply our knowledge of molecular and cellular biology to understand and reverse human disease. Regenerative medicine is an emerging field that aims to revolutionize the treatment of disease by providing cures rather than treating symptoms. It relies on multidisciplinary approaches that require expertise in diverse areas. Approaches include the use of stem cells to provide limitless supplies of cells for transplant therapy and disease modeling, bioengineering and tissue engineering to generate replacement tissues and organs and the production of transgenic animals to study the fundamental molecular basis of organ formation and disease. The department has active research programs in tissue fabrication and bioengineering, developmental biology, cardiovascular disease, digestive and liver disease, cancer biology, cell signaling and drug development. The department is also heavily involved in biomedical education through the training of medical and graduate students. Regenerative medicine is at a particularly exciting stage, with investigators being poised to make discipline-changing advances of high impact. The field is on the cusp of revolutionizing biomedical science, and as regenerative medicine researchers, we are limited only by our imaginations. Please, visit the department online at https:/