Drug discovery efforts that started in zebrafish are moving closer to clinical development.
La Jolla Pharmaceutical Co. and Vanderbilt University have signed a research and license agreement covering Vanderbilt’s research program and intellectual property rights related to compounds that block bone morphogenetic protein (BMP) type-I receptors. The compounds have therapeutic potential in a broad range of diseases, including rare genetic disorders.
BMP type-I receptors play diverse roles during mammalian development and in adult physiology. Aberrant activation of a specific BMP receptor — because of a genetic mutation — causes the rare disorders fibrodysplasia ossificans progressiva (FOP), which immobilizes its sufferers by turning their soft tissue into bone, and diffuse intrinsic pontine glioma, an aggressive pediatric brain tumor.
BMP receptor inhibitors, such as those being developed at Vanderbilt, hold promise not only for these rare disorders, but also for other diseases including Duchenne muscular dystrophy, anemia and multiple types of cancer.
“We’re very excited about the possible indications for these compounds,” said co-principal investigators Charles Hong, M.D., Ph.D., associate professor of Medicine, and Corey Hopkins, Ph.D., assistant professor of Pharmacology and Chemistry at Vanderbilt.
Hong and his colleagues identified the first BMP receptor inhibitor, which they named dorsomorphin, in a screen for compounds that disrupted front-and-back patterning during zebrafish development.
Their 2008 report about dorsomorphin launched the current drug discovery program.
At Vanderbilt, medicinal chemists Hopkins and Craig Lindsley, Ph.D., have focused on synthesizing new compounds that selectively block specific members of the BMP type-I receptor family. Hong and Daniel Perrien, Ph.D., assistant professor of Orthopaedic Surgery and Rehabilitation, are testing the compounds in a variety of animal and cellular models.
Michael Villalobos, Ph.D., manager of Biotech Licensing in the Vanderbilt Center for Technology Transfer & Commercialization, facilitated the agreement with La Jolla.
Working with La Jolla, Vanderbilt investigators will identify the best drug candidates for application to the Food and Drug Administration and clinical testing.
“Developing new drugs is a very difficult and expensive thing to do,” Hong said. “We have a long and challenging road ahead of us, but based on every indication so far, we are optimistic we will be successful.”
“We are excited to see our work move forward from a basic science research program to a therapeutic program in partnership with La Jolla,” Hopkins said. “Together, we see this as an opportunity to position our BMP inhibitors as potential treatments for rare and neglected diseases.”
The Vanderbilt team credits Fred Kaplan, M.D., chief of the Division of Molecular Orthopaedic Medicine at the University of Pennsylvania and a world authority on FOP, with raising awareness about the potential of compounds like dorsomorphin for FOP.
The VU team also noted the critical role that funding from the FOP community, particularly the Cali family of New Jersey, has played in supporting their research and moving the drug discovery efforts forward.
And while clinical indications may begin with rare diseases like FOP, studies have suggested that BMP inhibitors might be useful for a range of diseases, including many different types of cancer.
“It’s intriguing that a therapy designed for a small population — patients with FOP — may actually benefit a much larger group,” Hong said. “One of the joys of research is discovering and developing something that has the potential to impact human lives.”
“In collaboration with our innovative partners at Vanderbilt University Medical Center, we will work hard to translate their pioneering discoveries into novel treatments for patients in need,” said George F. Tidmarsh, M.D., Ph.D., president and chief executive officer of La Jolla.
Under the research and license agreement, La Jolla will fund further research in the BMP receptor inhibitor program at Vanderbilt in return for worldwide rights to compounds emerging from the program.
