Yale Researchers Awarded Grant to Develop Treatment of Williams Syndrome

Yale researchers have been awarded a $320,000 grant from The Kiev Foundation to study new ways to treat Williams Syndrome, a rare, thus far incurable chromosomal disorder that causes cardiovascular and connective tissue problems.

Williams Syndrome (WS) occurs in about 1 in 10,000 births. It is caused by the deletion of genes on chromosome 7. Characteristics of Williams Syndrome can include a flattened nasal bridge and small, upturned nose, prominent lips with an open mouth, puffiness around the eyes, an unusually cheerful personality, strong musical ability, attention deficit disorders, developmental delays, slack joints, and complications in blood flow due to thickened arterial walls, including those of the large artery that leaves the heart.

The Kiev Foundation grant will support the research of Frank Giordano, M.D., associate professor of internal medicine (cardiovascular); William C. Sessa, professor and vice chair of the Department of Pharmacology and director of the Vascular Biology and Therapeutics Program; and George Tellides, M.D., professor of surgery (cardiothoracic), who will study the elastin gene in order to design new treatments for Williams Syndrome. The most severe problems of WS are caused by the loss of one copy of elastin, a gene on chromosome 7 that plays a key role in the maintenance of artery walls.

Giordano and Sessa will investigate whether the deletion of one copy of elastin causes changes in gene expression that lead to WS. Giordano’s lab will attempt to engineer transcription factors as a treatment to increase the expression of the remaining elastin gene. Sessa’s lab will concentrate on identifying microRNAs that can enhance that expression.

“Our work through this grant could benefit not only Williams Syndrome patients, but those suffering from other connective tissue disorders as well,” Giordano said. “The approaches we are using may also help other patients suffering from genetic diseases in which only a single copy of a normal gene is present.”

Tellides will study the pathways that involve a key protein complex, mTORC1, which is activated in dividing cells. Smooth muscle cells from arteries of WS patients divide faster than normal and contribute to the blockage of blood vessels. He will test whether inhibition of these pathways may provide a suitable treatment for WS patients.

“Drugs that inhibit mTORC1, such as rapamycin, are currently used in heart transplant patients and also to coat metal stents that open blocked coronary arteries,” Tellides explained. “They may represent a novel therapeutic modality in Williams Syndrome and avoid the need for heart surgery in affected babies.”

“We are very fortunate to have the support from The Kiev Foundation to tackle this important clinical problem from different perspectives,” Sessa said. “Our approach is feasible and a potentially new approach to enhance elastin gene expression.”

The Kiev Foundation has made a commitment to promote groundbreaking research on new treatments for Williams Syndrome. The Foundation partners with the Williams Syndrome Association to stimulate interest in cross-disciplinary research on this disorder.

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Helen Dodson: helen.dodson@yale.edu, 203-436-3984