Small Molecules to the Rescue

June 8, 2007 -- Many of the diseases of aging, such as heart attack and peripheral artery disease, share a common characteristic: they involve the death of tissue when its blood supply is cut off. Edward Botchwey, an assistant professor of biomedical engineering, investigates ways to restore that blood supply, ideally preventing the damage these diseases cause and helping to regenerate replacement tissue. His method of choice: small therapeutic molecules.

Researchers typically rely on larger peptide-based molecules to promote revascularization, so Botchwey is breaking new ground. “The use of small molecules for drugs and other therapeutic agents offers a number of compelling advantages,” he explains. Small molecules can more easily be transported and delivered to precise locations within the body, and they tend to retain their beneficial activity longer than larger molecules. They are also usually cheaper and simpler to manufacture, an important consideration, Botchwey points out, when you are trying to interest a private company in producing them.

Botchwey’s choice reflects the emphasis within the Department of Biomedical Engineering on translational research, or targeting breakthroughs in basic research that can readily be developed into therapies delivered at the bedside.

Botchwey’s group developed the first synthetic small molecule capable of stimulating the growth of blood vessels, SC-3-149. Under specific circumstances, SC-3-149 can be delivered to sites of injury to promote revascularization and enhance formation of musculoskeletal tissues like bone and ligament. “For someone with my interests, this is a very promising molecule,” he says.

Botchwey’s research is also fueled by significant advances in the study of a naturally occurring small molecule growth factor involved in revascularization, S1P (sphingosine-1-phosphate). Kevin Lynch, a professor of pharmacology, and Timothy Macdonald, a professor of chemistry and pharmacology, have created a library of S1P receptor agonists and antagonists, molecules that mimic or block the action of S1P, giving Botchwey a number of candidates for more precisely controlling the formation of new microvascular networks.

The implications of Botchwey’s work for bone regeneration are striking. Working with joint reconstruction specialists in the Department of Orthopaedic Surgery, Botchwey and his colleagues are developing new therapies for treatment of femoral osteonecrosis, a condition caused by damage to the vessels feeding the thigh bone, whether from trauma or from such nontraumatic causes as steroid use, infection, radiation, and diabetes. Osteonecrosis can be very difficult to diagnose early; often by the time it is found, patients require a total joint replacement.

“This is an ischemic disease much like a heart attack,” Botchwey comments. “You could regenerate the necrotic bone with an angiogenesis strategy based on small molecules and avoid surgery. Ultimately, you may be able to apply the same strategy to heart attack and peripheral vascular disease.”

Written by Charlie Feigenoff, a freelance writer in Charlottesville.