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Funding, interest lag in sickle cell disease fight

Dr. Willis & Pamela Lonzer with their daughter Camille, who has sickle cell disorder, at their home in Chicago. Credit: Anne Ryan for STAT
Dr. Willis & Pamela Lonzer with their daughter Camille, who has sickle cell disorder, at their home in Chicago. Credit: Anne Ryan for STAT(Anne Ryan)

Dr. David Williams very much hopes the White House’s $755 million “Cancer MoonShot” finds cures, that Sean Parker’s $250 million “Dream Team” brings effective immune-system treatments to every kind of tumor, and that the $370 million raised by Hollywood-based Stand Up to Cancer fuels discoveries that make malignancies as treatable as headaches.

All Williams wants is $5 million — a rounding error to the billionaires making nine-figure donations to cancer research — to run a clinical trial that has a good chance of curing sickle cell disease.

There is no moon shot for sickle cell. There are no “ice bucket challenges.” When fund-raisers at Boston Children’s Hospital and Dana-Farber Cancer Institute, where Williams is president of the Cancer and Blood Disorders Center, ask donors to support sickle cell research, benefactors say they prefer to fund efforts that promise to help the adorable little kids stricken with cancer.

There are many theories about why that is, and why the lack of urgency and even interest extends to scientists. Fewer than a dozen US labs are working all-out on sickle cell disease, Dr. Stuart Orkin of Boston Children’s said. “I’m not sure why there are so few,” he said. “Maybe [the biology of sickle cell disease] seemed too simple, or maybe it isn’t sexy enough.”

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In the United States, the disease most frequently affects blacks. It also is found among people of Mediterranean, African, Middle Eastern, or Asian Indian backgrounds.

“Sickle cell patients have never been at the front of the line,” said Dr. David Nathan, 87, a past president of Dana-Farber who helped discover the only drug that partly treats it. “It strikes Italians, Greeks, blacks. . . . This work, especially clinical trials, is hugely expensive, and the National Institutes of Health and private foundations haven’t prioritized it.”

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Virtually every scientist thinks the disease he or she studies is underfunded. What’s different about sickle cell is that scientists can point to specific turning points when a few more people in the lab would have speeded the pace of progress, and to specific studies that might, with a national effort, cure the disease.

“This is the right time for a sickle cell moonshot, a concerted effort to focus resources — not just financial resources but intellectual resources — on a goal,” said Williams. “The technology has advanced to the point where we can talk about curing this disease.”

‘I try not to think about it’

Every year about 300,000 babies around the world are born with sickle cell disease, due to a mutation in the gene for hemoglobin, the oxygen-carrying molecule in red blood cells. Only infants who inherit a defective gene from both parents — an estimated 100,000 people in the United States — have it.

The mutation, discovered in 1956, causes red blood cells to cramp up into a crescent shape that makes them clump, impeding their flow through blood vessels. As a result, patients can suffer anemia, infections, fatal organ failure, tissue damage, strokes, and pain so intense it feels like a pickax-in-the-skull migraine everywhere in the body.

Camille Lonzer had her first such sickle cell crisis, as the severe pain is called, a year ago, when she was 13, the latest blow from a disease that for years had sent her to the hospital with fevers and infections seemingly as often as other little girls go to birthday parties.

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Her parents, who work for pharmaceutical companies near Chicago, have been tireless in managing Camille’s sickle cell, including massaging her in an effort to keep her blood flowing and the pain at bay. So far, the disease has not kept Camille “from doing everything I want,” she said. But the arrival of the pain crises might change that.

“I try not to think about it,” she said. “I try to imagine myself somewhere else.”

Camille began taking hydroxyurea after the pain crisis. Hydroxyurea is an old cancer medication whose effect on sickle cell was discovered serendipitously by Nathan and his colleagues. It can reduce episodes of sickle cell crisis, but helps only about half of patients, can cause serious side effects, and does nothing about the sickling itself.

A bone marrow transplant can cure the disease, but most patients can’t find a match, the procedure has a fatality rate of up to 5 percent, and patients need to be on anti-rejection drugs forever.

While other discoveries of disease-causing mutations led to treatments and even cures in, for example, 26 years for cystic fibrosis or 16 years for HER2-positive breast cancer, the discovery of the sickle cell mutation has led to exactly zero after 60 years.

Not that there haven’t been opportunities.

Missed chances

Physicians had long been struck by how some people with the sickle cell mutation have few or no disabling symptoms. In 1948 scientists guessed why: These patients were still making a form of hemoglobin that the body ordinarily stops producing in the first year of life. If just 15 percent or so of the body’s hemoglobin is “fetal hemoglobin,” scientists learned, it keeps the disease at bay.

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Orkin began searching for the DNA magic that kept production of fetal hemoglobin turned on.

He and his colleagues got clues by studying Saudi Arabian patients who made fetal hemoglobin into adulthood. But the genetic basis of that is “complex,” Orkin and his colleagues wrote in 1989.

It wasn’t a warning that the genetics of sickle cell were too tough to decipher. It was what, in many other fields, would be taken as a challenge, drawing young scientists to an intriguing puzzle. That did not happen.

By the late 1980s, scientists knew that genetic on-off switches — transcription factors — regulated the switch from fetal to adult hemoglobin, said Orkin, who is also chairman of pediatric oncology at Dana-Farber. By sheer bad luck, his and other labs that set out to identify those molecules looked in the wrong cells. The field didn’t have the critical mass that might have led someone to figure out what kinds of cells to use in experiments seeking the fetal-to-adult switch.

They hit dead end after dead end, and with little incentive to keep hunting, “we went off and did other things,” said Orkin. “Sickle cell wasn’t working.”

He spent the 1990s on the genetics of normal blood cell development. He still thought about sickle cell, and the genetics of the fetal-to-adult hemoglobin switch. But no one was banging on his door to fund sickle cell research.

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In the early 2000s, Harvard medical student Vijay Sankaran told Orkin he wanted to study the fetal-to-adult hemoglobin switch. Orkin asked if Sankaran was sure; he worried that Sankaran’s budding career would tank as a result of searching fruitlessly for the molecular genetics of sickle cell. His caution seemed to be borne out when, for nearly three years, Sankaran’s experiments repeatedly failed. It turned out he was looking for the crucial transcription factor gene on the wrong chromosome.

Sankaran finally bagged his quarry in 2008, when he — with others in Orkin’s lab — identified the gene that turns on production of adult hemoglobin. Called BCL11A, it’s on chromosome 2. When they suppressed BCL11A in human cells growing in lab dishes and in mice, they reported in Science in 2011, blood cells kept making fetal hemoglobin and the mice were cured of sickle cell.

That opened the door to using gene therapy to cure sickle cell.

“We didn’t scream enough”

When David Williams was a newly minted physician 30 years ago, Children’s Hospital hematologists saw about as many kids with hemophilia as kids in sickle cell crisis. Since then, hemophilia treatments have become so successful that children almost never show up with uncontrollable bleeding.

“So we see almost all sickle cell,” Williams said, explaining why he jumped at the chance to build on Orkin’s discoveries.

He began developing an experimental therapy to knock out enough BCL11A to reactivate some fetal hemoglobin production.

He needed a way to slip genetic material into cells, using a harmless virus. It took his lab two long years to figure out how to do that safely. “I had only one postdoc working on it,” Williams said. “With more people, it would have taken much less time.”

His plan is to pack molecules called antisense RNAs into lentiviruses, which are as efficient at delivering genetic material into cells as pizzerias are at delivering menus into apartment-house vestibules. The viruses would carry the RNA into blood stem cells isolated from a patient’s bone marrow. Antisense RNA basically hogties the messenger molecules that carry instructions from the BCL11A gene, triggering a sequence of events that should keep at least some cells making fetal hemoglobin rather than switching to the adult form.

Gene therapy would likely be too expensive for use in India and the African countries where sickle cell is common, so Orkin hopes a drug could be developed to tie up BCL11A. “That’s where I think a moonshot really is needed,” he said: to draw clever, imaginative biologists and chemists to find molecules that can disable enough BCL11A to keep enough cells making fetal hemoglobin to cure the disease.

No one minimizes the long, hard slog that would take.

The what-ifs — if 50, not 10, labs pursued sickle cell; if Orkin had been able to enlist more scientists in the 1990s transcription-factor hunt; if Williams had had the resources to support four or five postdocs looking for a safe vector — are impossible to answer. But “as a scientist and a physician, it’s one of my major frustrations,” said Williams.

“Maybe it’s our fault,” said Nathan about the paucity of resources devoted to sickle cell over the decades. “Maybe we didn’t scream enough” for more funding, more bodies, more attention. “But it’s just not right” how little attention the disease gets.

Pamela Lonzer seconds that. When Camille, her daughter, was born with sickle cell disease, “I thought my world was ending,” she said. Although Camille has participated in research on exercise and pain, the family is still waiting for a clinical trial of a therapy that might actually cure her.

“This is a disease that doesn’t get the attention or the funding it should,” Lonzer said. “There’s a stigma that comes from thinking it affects only African-Americans.’”

The American Society of Hematology plans to call for a sickle cell moonshot this fall. The group can do little more than make that plea to the public, elected officials, and the NIH, whose National Heart, Lung, and Blood Institute funds sickle cell research. But the institute also funds research on heart disease, which has a much larger constituency. “I am not holding my breath,” Orkin said.

Williams is slowly getting approvals for the small clinical trial he’s planning. He thinks a moonshot might organize multiple medical centers to participate in both this trial and, if it succeeds, larger ones. He hopes to start recruiting patients in September.

“This is absolutely going to work,” Williams said — if only someone would pony up $5 million.


Sharon Begley can be reached at sharon.begley@statnews.com. Follow Begley on Twitter @sxbegle