Finding new treatments for human diseases is a challenging, lengthy, and costly endeavor. For every drug that makes it through the drug discovery and development process, hundreds of candidates fail and vast amounts of money are spent without any direct return on investment. In order to make the discovery process more efficient, scientists have begun to reexamine existing drugs and compounds—whether they are in development or are already on the market, or have failed clinical trials due to lack of efficacy. The goal is to find new applications for these compounds.
Scientists at Sanford-Burnham Medical Research Institute (San Diego, CA, and Orlando, FL) have embarked on a mission to create the world’s most comprehensive drug library, with the goal to find new uses for them. With bi-coastal drug discovery operations in California and Florida, Sanford-Burnham will build, house, and maintain the library. In addition, researchers at the Institute are using “disease in a dish” stem cell models to test the efficacy of these against a number of human diseases and intend to share access to the library with other institutions across the nation so that they can do the same.
Advantages of drug repurposing
Figure 1 – Close-up view of Kalypsys (San Diego, CA) 1536 well washer/dispenser tip head as it dispenses cells for a high-content assay at Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics.
There are many benefits to drug repurposing. In short, it is safer, faster, and less expensive than starting from scratch. Since a repurposed drug has already passed a significant number of toxicity and other tests, its risks are better known and the chance of failure due to adverse side effects is reduced (Figure 1). More than 90% of drugs fail during development, contributing to the high cost of pharmaceutical research and development. Repurposed drugs bypass much of the early cost and time needed to bring a drug to market. Ultimately, a new therapy based on a repurposed drug could benefit patients sooner—saving and improving more lives.
Finding new indications for existing drugs has been successful in a number of past cases. For example, the agent thalidomide was originally indicated for morning sickness, but was more recently approved as first-line treatment for leprosy and multiple myeloma. Minoxidil, initially developed to alleviate high blood pressure, was found to cause significant hair growth and is now prescribed under the trade name Rogaine® (McNeil-PPC, Fort Washington, PA). Similarly, the drug gabapentin, used initially as an anticonvulsant, was later found to be effective in the treatment of neuropathic pain.
While we are making substantial progress, one challenge is the incompleteness of the current drug library available to us. It helps that the NIH (Bethesda, MD) recently made a comprehensive listing of clinically approved drugs available. The NIH is also currently working directly with pharmaceutical companies to find new uses for once-promising drugs that have been set aside by the industry. However, the larger the library of available drugs, the greater the chance we will find those that can be repurposed to prevent or treat a devastating disease.
Testing repurposed drugs with “disease in a dish”
Figure 2 – One of three Stäubli (Windsor, CA) RX160 robot arms at the Conrad Prebys Center for ultrahigh-throughput screens.
Despite the promise of drug repurposing, serendipitous discovery of new applications for existing drugs happens rarely. With the advent of “disease in a dish,” researchers can now test large numbers of approved drugs for their efficacy against a number of diseases before they reach clinical testing in humans. In this technique, researchers at Sanford-Burnham and elsewhere take skin samples from a patient or healthy volunteer, dial them back developmentally to stem cells, and induce their differentiation into the desired cell type (neurons, for example, if studying Alzheimer’s disease). The advantage to disease-in-a-dish modeling is that it generates large numbers of otherwise hard-to-access cell types, complete with an individual’s genetic and epigenetic makeup.
There has already been success combining a disease in a dish and repurposed drugs. Using a small library of FDA-approved drugs and a disease-in-a-dish model created with cells from a patient with a rare form of muscular dystrophy, Dr. Anne Bang, a scientist in the Sanford-Burnham Conrad Prebys Center for Chemical Genomics (La Jolla, CA) identified a series of agents that reverse the functional defect causing the disease (Figure 2). Spurred on by this exciting data, the team is now using disease-in-a-dish models to screen for drugs that could benefit other genetic diseases.
Drug repurposing for treatment of genetic diseases
Figure 3 – Schematic depiction of a possible approach to the integration of induced pluripotent stem cells and drug repurposing to accelerate personalized medicine for rare genetic diseases.
One area in which drug repurposing and disease in a dish has the greatest potential to revolutionize treatment and provide immediate hope for families is genetic disease (Figure 3). Of the 6000 or so known genetic diseases, only roughly 200 have any treatment options. For the remaining 5800, there is really no clear therapeutic option. The authors’ approach provides for the first time a rational, science-based systematic means to identify existing drugs that could be repurposed to treat rare diseases such as muscular dystrophy or congenital disorders of glycosylation (CDG).
A team led by Dr. Hudson Freeze, Director of Sanford-Burnham’s Genetic Disease Program, works closely with CDG children and their families. CDG results from faulty glycosylation, the process of adding carbohydrate chains to proteins and lipids. Carbohydrates are required for proper secretion and targeting of thousands of proteins, an often overlooked fact of biology, and children born with a defect in just one of the many required enzymes have a form of CDG. Finding a drug or other compound that corrects a CDG child’s glycosylation defect could provide a new therapy for this condition.
Parents of children with CDG or other rare diseases cannot afford to wait the 10–15 years it takes for a new drug to come to market if current therapies do not work for them. This makes drug repurposing appealing, since it begins with a drug whose safety profile is well-established and then simply develops an efficacy profile in a new indication. Compared to the making of a new drug, the time gain and reduction in attrition due to safety concerns or other unknowns make drug repositioning a sensible approach for patients and their caregivers.
Regrettably, pharmaceutical companies are reluctant to engage in drug repurposing efforts for many genetic diseases. This is in part because the patient populations tend to be small, making it a challenge to organize robust clinical trials. In addition, competition with generic drugs makes this effort commercially unviable, in spite of its great potential to benefit human health.
As a nonprofit biomedical research organization dedicated to translating biological research into treatments for human disease, Sanford-Burnham is in an ideal position to undertake this important endeavor. The Institute has, arguably, one of the most advanced drug-screening operations in the nonprofit world. Renowned principal investigators who have expertise in many diseases, and a number of clinical partnerships, provide Sanford-Burnham researchers with access to patient samples. Furthermore, the Institute has the infrastructure to generate stem cell-based disease-in-a-dish models, the technology to search for those drugs that might reverse the disease, and the expertise to put it all together.
In the short term, Sanford-Burnham seeks to generate personalized therapeutic options for children with genetic diseases. In the long term, the overall process outlined here has the potential to have much broader implications for personalized medicine and companion diagnostics in many disease areas.
Christian A. Hassig, Ph.D., is Director of Drug Discovery, and Michael Jackson, Ph.D., is Vice President of Drug Discovery and Development and Adjunct Associate Professor, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037, U.S.A.; tel.: 858-646-3100; fax: 858-646-3199; e-mail: email@example.com. Layton H. Smith, Ph.D., is Director of Drug Discovery and Assistant Professor, Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Rd., Orlando, FL 32827, U.S.A.; tel.: 407-745-2000; fax: 407-745-2001; e-mail: firstname.lastname@example.org.