As a child, the pain crises of his sickle cell disease often landed Stephine McCants in the hospital for weeks at a time. “I didn’t know how to deal with it,” he says. “I used to blame God. I used to blame everything -- because the pain would be that bad.” Now McCants, 28, says the pain today is duller, though more frequent. The Philadelphia musician only ends up hospitalized once or twice a year. He takes medication, works out hard, drinks lots of water, and eats a healthy diet. He gets frequent massages from his sister, a massage therapist, and tries to avoid getting cold and wet, which he says can trigger an attack. Still, he knows that the sticky, pointed red blood cells that course through his bloodstream are likely to cause more problems as he ages. Most people with sickle cell end up with organ damage caused when the misshapen cells clog blood vessels and tiny capillaries. Average life expectancy is far shorter than for people without the disease. And until recently, the only available treatment for sickle cell was the same as it had been for decades. But change is coming for people like McCants. In mid-November, the second drug in 3 years was approved to treat the symptoms of sickle cell. Dozens of clinical trials are underway, testing several other potential treatments. The federal government and the Bill & Melinda Gates Foundation recently announced they would each contribute $100 million to provide effective sickle cell and HIV therapy in the developing world. And groups of scientists are testing gene therapies that offer a potential cure for sickle cell. Reginald French, president and CEO of The Sickle Cell Foundation of Tennessee, says he’s thrilled with all the scientific attention to sickle cell. “Anytime you can produce anything that’s new to help relieve some of the pain and suffering, I think it’s going to be a major improvement,” says French, who does not have the disease himself. “There’s a tremendous amount of hope that the year 2020 is going to be a very good year for the sickle cell community.” “It’s really good, but it’s so long overdue,” he says. A Long Time Coming Sickle cell was the first disease understood at the molecular level. In 1949, chemist Linus Pauling, who would go on to win two Nobel Prizes, co-authored a paper in Science offering the first-ever proof that a human disease was caused by an abnormal protein. A genetic mutation inherited from both parents caused defects in the hemoglobin protein found in red blood cells. But identifying the problem and solving it are two different things. And some say the search has been slowed by the fact that most sickle cell patients are low-income minorities. Cystic fibrosis, another inherited condition with less than one-third the number of American patients, has received vastly more research funding than sickle cell -- as much as 11 times more in some years, according to a 2013 study. Sickle cell patients are mostly African-American; cystic fibrosis patients are not. “I don’t know if that’s the sole reason” there’s been such a difference in research funding, French says, “but I do believe that’s a top contributing factor.” The lack of biological understanding has also been a limiting factor, says David Altshuler, MD, chief scientific officer of Vertex Pharmaceuticals. There is no obvious way to get a body to start making healthy red blood cells. The only known cure for sickle cell disease is a bone marrow transplant, ideally from a healthy, matched sibling. But only about 15% of patients have a sibling who meets the criteria. And bone marrow transplants remain arduous and risky, with death rates of as much as 5%. Finally, researchers say, genetic sequencing, a deeper understanding of the biology of sickle cell, advances in gene therapy, and federal changes that made it more financially rewarding to develop drugs for rare diseases have made advances possible. For example, the newest drug approved to treat sickle cell, Adakveo from Novartis, builds on the discovery of a protein called P-selectin that lines the inside of blood vessels, making them sticky. This stickiness is useful to stem bleeding in case of an injury. But in people with sickle cell, it makes a bad situation worse, raising the risk that red blood cells will clog vessels and decrease blood flow. Blocking this sticky protein -- as Adakveo does -- helps reduce pain crises by 50% and may improve blood vessel health long-term, says Julie Kanter, MD, an associate professor, hematologist, and director of the adult sickle cell center at the University of Alabama School of Medicine in Birmingham. “I think it’s a game-changer in so many ways,” says Kanter, who helped run one of the recent Adakveo trials in adults and is now leading research to see if the drug works as well in children. Kanter says she likes that patients can get Adakveo via an IV rather than pills, which -- between painkillers, folic acid, ibuprofen, hydroxyurea, and other medications -- they take too many of already. They’re coming in for lab tests once a month anyway, so it won’t be a burden to give them the medication, she says. She and others hope that Adakveo will work even better when paired with the standard-of-care drug hydroxyurea, which helps prevent formation of sickled cells, or some of the other treatments coming to market. “We as providers treating patients with sickle cell couldn’t be happier to have a targeted therapy to offer our patients,” Kanter says. Hopes for a Cure Gene therapy offers the potential for a cure. In a pilot gene therapy trial for sickle cell and a similar disease called beta thalassemia, Vertex and CRISPR Therapeutics announced in mid-November that the first two people whose genes were edited with a new technique called CRISPR have fared well, having only temporary and treatable side effects. Boston Children’s Hospital has treated five people so far with a different approach that doesn’t use CRISPR, but has the same effect. Since the treatment, all five have been able to forgo the blood transfusions they had needed monthly for years. But gene therapy won’t be easy for patients -- at least for the foreseeable future. With gene therapy, some of the patient’s red blood cells are withdrawn, and in a lab, their genes are altered either to correct the mistake that causes sickle cell or to turn off a gene called BCL11A. Tamping down BCL11A allows the body to resume making fetal hemoglobin, which should serve as a cure. Fetal hemoglobin is made in in the womb and for the first few months after birth. People with sickle cell who have a mutation that allows them to continue making fetal hemoglobin throughout life have few or no sickle cell symptoms. So restarting fetal hemoglobin with drugs or gene therapy should inhibit or prevent sickle cell symptoms. To make room for the new, healthy cells, the patient must have at least a few days of chemotherapy to kill off their sickled red blood cells. In a gene therapy trial at Boston Children’s Hospital, patients stay in the hospital for more than a month as their red blood cells are destroyed and rebuilt. Doctors hope this time can be cut by a lot once the experimental treatment is federally approved. But it’s still a daunting, expensive process that’s not feasible in most of the developing world, which lacks the infrastructure to provide such care. That’s one of the major problems the Gates-government collaboration will have to solve to bring a sickle cell cure to sub-Saharan Africa. Representatives with the National Heart, Lung, and Blood Institute agree that it will be a long process -- they figure on 7-10 years. But better to start that clock ticking now than in 5 years, says Amy Patterson, MD, the federal agency’s chief science adviser and director of scientific research programs. Someday, according to Patterson and Keith Hoots, MD, the director of the agency’s Division of Blood Diseases and Resources, it should be possible to provide the entire treatment inside the body: safely tinkering with the genes of the red blood cells and enabling healthy ones to take over. The treatment will also have to work in young children, the two acknowledge, because in sub-Saharan Africa, where sickle cell is most common, more than half of those born with the disease don’t survive past their fifth birthday. “This is not a trivial process,” Hoots says. Sometime early next year, the agency will announce the first research opportunities for scientists interested in helping reach this lofty goal. Another limiting factor for expanding the reach of treatment: cost. Prices won’t be set for gene therapy in sickle cell until after the approach receives federal approval. But Luxturna, a gene therapy to treat a rare form of blindness, costs $850,000 for a one-time treatment. Zolgensma, a gene therapy for a muscle-wasting disease called spinal muscular atrophy, comes with a $2.1 million price tag. Although hydroxyurea, the drug most patients are prescribed, isn’t expensive by American standards, it’s still unavailable in much of the developing world, because patients have to be monitored regularly. And newer drugs often come with astronomical price tags, though drugmakers argue that they will pay for themselves long-term, by reducing complications. Endari, which was approved in 2017 and helps relax stiff red blood cells, costs about $3,300 a month and isn’t covered by many insurance plans. For Adakveo, most American patients would be charged between $7,000 and $9,500 a month, though out-of-pocket costs to individual patients will be far less, according to Novartis, which is negotiating with public and private insurers to cover the drug. Novartis promises to do what it can to make the drug available in lower-income countries. Living with the Disease Isn’t Easy Despite all the promise, it remains extremely difficult to live with sickle cell, says Mitchell Weiss, MD, chairman of the Hematology Department at St. Jude Children's Research Hospital in Memphis, TN. “The system is not set up to take of these patients,” he says, because it’s not a money-maker for hospitals. Most health care providers are extremely dedicated but simply don’t have the resources they need to provide the best care possible, Weiss says. Medicaid reimbursements are low, and people with sickle cell have lots of needs. “Good care is not compatible with the way our health system runs these days.” Patients can have very different experiences, depending on several things, including where those sickled cells get stuck. Some children can have strokes, leaving them with lifelong neurological problems, Patterson says. Others can have kidney failure, heart and lung trouble, joint damage, retinal detachments -- or some combination. That means treatment must be personalized, too, with access to lots of different specialists, as well as care coordinators, social workers, and psychologists so patients can remain productive members of society, says Farzana Sayani, MD, an adult hematologist and director of the comprehensive sickle cell program at the Hospital of the University of Pennsylvania, where McCants gets his care. Matthew Heeney, MD, of Boston Children’s Hospital, says part of the problem is how symptoms come and go. “Ninety-five percent of the time, you look like everyone else. Five to 10% of the time, you’re 100% disabled.” That, he says, means patients don’t meet criteria to receive federal disability assistance, even though it may be impossible for them to work. McCants says he used to work in retail, which was tough when a pain crisis could come on at any time. He was able to get permission to wear a hoodie to work, so he could stay warm, but then he’d have to reveal his condition to his supervisors, most of whom were supportive. “When you have bosses that see you go through that pain and that you’re in the hospital, you do get accommodations,” he says. But he’s also had the opposite experience. Like many with sickle cell, he’s been treated as if he were someone with a drug addiction seeking a fix. One hospital that he’ll never return to left him sitting in the emergency room for hours, he says, even though he was unable to move and weeping with “like 10 to the 10th power pain,” he says, referring to the pain chart that tops out at 10. “The fact that people with sickle cell are looked at a certain way and we have an actual disease that we are born with -- it pisses me off, it really does,” McCants says. He says he’s glad there’s more attention being paid to people who have sickle cell now, and he hopes that better treatments and cures are coming soon. But he remains skeptical and hesitant to try them himself. The disease is awful, he says, using a more colorful term to describe it. “But there are people here going through a lot, lot worse,” McCants says. “My family is taken care of. That’s all I really care about.” Source
