Chloe Kiev, an otherwise perfect baby, was born with a troubling trait—a very loud heart murmur. It was so loud, in fact, that when a cardiologist did an echocardiogram he immediately recognized Chloe’s condition, which was later confirmed genetically. She has Williams syndrome.

Williams syndrome, named for the New Zealand cardiologist who first reported it in 1961, is a rare genetic disorder that affects a child’s appearance, cognitive development, and physical health. A heterozygous deletion syndrome, it is caused by the absence of one copy of between 26 and 28 genes from the long arm of chromosome 7, resulting in cardiac, vascular, digestive, and cognitive abnormalities. The cardiovascular problems are linked to the loss of the elastin gene, ELN, which codes for a protein called tropoelastin, the precursor of the elastin that gives blood vessels their elasticity. People with Williams syndrome are susceptible to supravalvular aortic stenosis (SVAS), a narrowing of the large blood vessel that carries blood from the heart to the rest of the body. Patients are also vulnerable to hypercalcemia, feeding difficulties, small stature, small widely spaced teeth as well as cognitive and behavioral issues, and are hypersensitive to certain sounds. They have such distinctive facial features as a broad forehead, a short nose, full cheeks, a wide mouth, dental malocclusion, and small widely spaced teeth. These children typically have mild to severe learning disabilities, and developmental delays, along with endearing personalities and an affinity for music.

The Kievs felt isolated after Chloe was diagnosed. Beyond the stress of caring for a child who needed heart surgery within the first six weeks of her life, who had severe colic, refused to eat, and would drink a bottle only as she slept, the Kievs felt that they had nowhere to turn.

Williams syndrome is what is known as an orphan disease—it afflicts about one in every 7,500 to 10,000 live births worldwide—or fewer than 20,000 people in the United States. Until recently these diseases, with their small potential markets, garnered little attention or financial support, but that is changing. Once the province of small biotech companies, orphan diseases have begun to pique the interest of big pharma because of their high cost and subsequent returns—$200,000 to $500,000 per patient. And in 2009 the NIH launched the Therapeutics for Rare and Neglected Diseases program, which budgeted $24 million to create a drug development pipeline for rare illnesses. But it has often fallen to families of patients with rare diseases to advocate and raise money for research. Chloe’s father Marshall recalls talking on the phone with a friend while his wife Johanna fed Chloe. “My friend asked, ‘So what are you going to do about this?’ I had never thought about doing anything other than take Chloe to the doctor, but then I thought, maybe there is something more we can do,” Marshall said.

The couple tasked the Kiev Foundation, a foundation funded by the Kiev family and dedicated to charitable works, with promoting research on Williams syndrome that might be applied to other conditions and disorders as well. The couple also created a separate foundation for Williams syndrome research called Chloe’s Quest, financed by the Kievs and a group of their friends. In 2008 a symposium at Yale funded by Chloe’s Quest brought together a multidisciplinary group of biomedical researchers to brainstorm ideas for research that could help advance the search for therapeutic options. The couple also invited the researchers to submit proposals for projects they would then support. Selected proposals, among them three from Yale scientists, received grants in 2009 from the Kiev Foundation. The couple closed Chloe’s Quest after the Yale symposium, preferring to work through the Kiev foundation.

“We didn’t have enough money to fund them all, but we got them to work together, to share postdocs, to compare notes, and help each other along the way,” Marshall Kiev recalls. The three teams received $360,000 for two years plus additional $150,000 for a one-year extension. As the Kievs got more involved with the Williams Syndrome Association, a parent support network headquartered in Troy, Mich., the association learned of the Yale research efforts and allocated resources for project extension grants.

Meanwhile, the Kievs learned as much as they could about Chloe’s disorder as they learned to care for her. “I even read Genetics for Dummies,” laughs Johanna. Marshall, a member of the management team of a hedge fund in Stamford, Conn., consulted with his brother Jon, a thoracic surgeon.

A three-pronged attack

“Our research is very focused,” says William C. Sessa, PH.D., one of the researchers funded by the Kiev Foundation. “We follow leads like detectives.”

Sessa, the vice chair and Alfred Gilman Professor of Pharmacology, professor of medicine (cardiology), and director of the vascular biology and therapeutics program, works with other researchers to mount a three-pronged line of attack to identify novel approaches for potential therapeutics. Since many of the cardiovascular manifestations of Williams syndrome are caused by a decrease in the production of elastin, two research teams are focusing on increasing the patient’s elastin levels. The third team is concentrating on controlling abnormal proliferation of vascular smooth muscles, a common manifestation in Williams patients.

Sessa’s team targeted cells that normally degrade elastin in patients with Williams syndrome and SVAS. Sessa’s team found that by antagonizing microRNA 29—a small noncoding RNA molecule that normally targets the elastin messenger RNA (mRNA) and promotes its degradation—elastin mRNA levels increased and vascular function in tissue-engineered vessels improved. In collaboration with a company providing microRNA 29 antagonists, Sessa is treating mice that have only one copy of the elastin gene with the hope that the microRNA 29 antagonist will increase the amount of elastin produced to the levels of a normal mouse with two copies of the elastin gene.

In the second line of attack, Frank Giordano, M.D., associate professor of internal medicine (cardiology), and his team developed a zinc finger transcription factor—a protein that binds to a specific DNA sequence and can turn on the elastin gene. “In this disease, one copy of the elastin gene is totally deleted. The other copy is there, but it’s not capable of producing enough elastin to prevent the children from developing vascular diseases,” says Giordano. To address this condition—haploinsufficiency syndrome—Giordano’s lab engineered a protein that compensates for the missing gene by binding very specifically to the remaining copy of the elastin gene and turning it on to increase elastin production. Nevertheless, says Giordano, “delivering the zinc finger protein to enough cells to prevent vascular disease is a hurdle.” The next step is to figure out what percentage of cells must be reached by the zinc finger protein to be effective. “I’m excited about this approach, but delivery is something we’re still working on.”

The lead researcher on the third Yale team, George Tellides, M.D., PH.D., professor of cardiac surgery and of investigative medicine, is looking at obstruction of the aorta—a life-threatening problem for many patients with Williams syndrome. Tellides tested the immunosuppressant drug rapamycin (Rapamune) to see whether it would prevent that obstruction. “We used two methods,” he explains. “Using smooth muscle cells from patients with Williams syndrome, we observed that those cells divided faster than the control cells. When we added rapamycin, the division of cells was diminished.” Tellides’ lab further observed that when rapamycin was tested in mice, the mouse died within days if it lacked both elastin genes. If it lacked only one gene, it survived but had a smaller aorta.

The team then treated mouse mothers with rapamycin in the last few days of pregnancy and continued to treat the offspring with the drug after birth. They found that while the rapamycin didn’t prolong the survival of the mice, the aorta was larger and less obstructed. Next, Tellides wants to add another drug, Gleevec (imatinib), to see whether the anticancer medication will further inhibit the proliferation of the muscle cells.

Tellides says his research into elastin production has implications far beyond treating patients with Williams syndrome. “It could inform a process that affects almost everyone with age,” he says. “Most elastin is produced early in life; little is produced later. So in a sense, people with Williams syndrome are experiencing an accelerated form of the aging process. In older people, wrinkles are the visible effect of the underlying loss of elastin, but it’s also affecting the arteries, including the aorta, so the lessons we learn about Williams can be applied to everyone.” The inescapable truth is that everybody’s aorta is going to have insufficient elastin if they live long enough, Tellides says, “so our research into how to turn on elastin production becomes useful in preventing the degeneration of vasculature, which is increasingly recognized as a disease process with significant impact on the health of the geriatric population.”

That is a point that is often made by rare disease support groups and the families of patients with the diseases—that while the number of people with a specific orphan disease may be small, researching those diseases can lead to knowledge that may be useful in treating far more common conditions.

Barbara R. Pober, M.D. ’78, a clinical geneticist and professor of pediatrics at Harvard Medical School, says that while Yale researchers haven’t yet identified cures or treatments for Williams syndrome yet, “they’ve identified novel approaches and pathways that could ameliorate the symptoms. They’ve identified avenues that haven’t been tried before. I genuinely believe they can build on this work.” Pober, who has been caring for people with Williams syndrome since 1987, says there has been a real paradigm shift in the field of genetics. “It used to be that if you diagnosed somebody with Williams syndrome, you informed the family, handed them a pamphlet, and said good-bye. Now, parents are asking, ’How can we fix it?’ Parents see the urgency researchers don’t. They are driving the equation.”

According to the National Organization for Rare Diseases (NORD), the dearth of new drugs for rare diseases can be traced to the Kefauver-Harris Amendment, passed in 1962 in response to the thalidomide tragedy. The amendment required that all drugs approved for sale be proven safe and effective via rigorous scientific studies. While this legislation improved drug safety, proving efficacy drove up the costs to drug companies, which responded by focusing on the development of treatments for common diseases so that they could recoup their research and development costs and generate a profit. Rare diseases, of which there are more than 7,000 according to NORD, were largely ignored, or orphaned.

Leaders of rare disease patient organizations banded together and spoke out, calling for legislation to encourage the development of treatments for rare diseases. An article about orphan diseases in the Los Angeles Times in 1981 inspired an episode of Quincy, M.E., a television series about a medical examiner. In this episode the protagonist fights for orphan drug development in response to the case of a teenager with Tourette syndrome. According to NORD vice president Mary Dunkle, Quincy star Jack Klugman and his producers received an avalanche of letters, which they forwarded to patient advocates. Klugman went on to testify before Congress on behalf of the Orphan Drug Act, which was passed in 1983. The act offered incentives for the development of drugs to treat orphan diseases, including market exclusivity, tax credits, and fast-track approvals. Single-issue organizations sprang up to fill the void left by the reluctance on the part of pharmaceutical companies and other traditional research and development sources to work on drugs with so little profit potential.

“If they (the Kiev Foundation) didn’t provide the funding, we’d never be doing this work,” says Sessa. “This is the first basic research project to be funded by the Kiev Foundation. We’ve got our eyes on the prize, because we have to justify what we’re doing with the money. We’ve made a personal connection with the family, so I feel an incredible amount of responsibility to do what I can.”

“When you work with disease foundations and societies of families with affected members, there’s a strong personal connection for the researcher,” Tellides says. “I’ve always been influenced by clinical disease, but this is more personal. It’s inspiring to be a part of it.”

While Terry Monkaba, executive director of the Williams Syndrome Association, knows that a “cure” for Williams syndrome is still a long way off, she says the work being done at Yale is invaluable. “Ten years ago, when we asked families about their priorities, research was not high on their list. Now it’s number two. That change is a direct result of the work being done by Yale.” The top priority, said Monkaba, is direct support—programs that affect their children’s daily lives, like scholarships, financial aid, and special camps.

Monkaba says the value of researchers collaborating and sharing information is another lesson that has come out of the work Yale researchers are doing. But perhaps the most important one is how potentially synergistic the research is. “The type of gene deletion people with Williams syndrome have may be key to finding treatments for other more common diseases, other cardiovascular disorders, high blood pressure, and arterial sclerosis.” says Monkaba. “There are overlapping characteristics. That’s what makes Williams syndrome such a valuable research model.”

Marshall Kiev looks forward to the day when major funders like the NIH and the American Heart Association get on board, and he’s optimistic that they will as they learn more about what’s being accomplished through Kiev Foundation support. In the meantime, he says, “I feel like we’ve come out of the clouds. This experience has forced us to live in the moment; I’m much more present now. But I tend to be pretty optimistic. I think Chloe has got a great future.”