Sickle Cell Treatments Improve; Genetic Cure On The Horizon

WORTH WAITING FOR: Kwaku Ohene-Frempong of the Sickle Cell Disease Association of America says "gene therapy is the ultimate cure of sickle cell disease." Back in 1949, Linus Pauling determined that sickle cell disease-an inherited blood disorder that afflicts 1 in 400 African Americans-is caused by a defect in one of the genes that codes for hemoglobin. Now people with sickle cell disease are finally reaping the benefits of a half-century of research. Within the last two years, several treatments have been developed that attack the cause and the significant symptoms of the disease. Bone-marrow transplantation can now provide a true cure for a small percentage of people with sickle cell disease. Two animal models have been developed. And researchers harbor realistic hopes that genetic therapy could actually cure the majority of sufferers. SIGN OF A SYNDROME: A scanning electron micrograph of a sickle cell For many years sickle cell disease was called sickle cell anemia, but this is a term that researchers, physicians, and the sickle cell community now prefer to avoid. "I try to discourage people from using the term 'sickle cell anemia,'" explains Kwaku Ohene-Frempong of the Sickle Cell Disease Association of America. "It tends to isolate one of the features of the disease-anemia-and make it sound as if that is the disease. When you use the term 'sickle cell disease,' that means it's a syndrome and has many, many manifestations." -R.F. Pauling determined that the faulty gene in sickle cell disease codes for a defective hemoglobin molecule that forms long helical polymers when deoxygenated. These polymers result in red blood cells with abnormal sickle-like shapes, and these sickled cells clog capillaries all over the body. This results in anemia and the painful sickle cell "crises" that occur when organs are deprived of their blood supply. Until recently, treatment centered on merely alleviating the pain of the crisis. But that's changing. "At the moment there is research in drug development, there is research in bone-marrow transplantation, and there is research in gene therapy," notes Kwaku Ohene- Frempong, director of the Comprehensive Sickle Cell Center at Children's Hospital of Philadelphia and chief medical officer of the Culver City, Calif.- based Sickle Cell Disease Association of America. "All three areas hold tremendous promise." "I think it's a good time," agrees Martin H. Steinberg, a hematologist and associate chief of staff for research at the Veterans Affairs Medical Center in Jackson, Miss. "There's a lot of stuff on the horizon, where for years there wasn't very much." Within the next six months, the Food and Drug Administration (FDA) will likely approve the use of the drug hydroxyurea for sickle cell disease. "Hydroxyurea is a drug that's been available for 30 years, used in the treatment of certain malignancies," Steinberg points out. "Ten or 15 years ago, it was noticed that hydroxyurea affects the bone marrow of sickle cell patients in a way that permits the increased production of a hemoglobin type called fetal hemoglobin, and the higher the level of fetal hemoglobin in the blood, the more it prevents sickle hemoglobin from sickling." Steinberg participated in the clinical trials of hydroxyurea (S. Charache et al., Medicine, 75:300-26, 1996), and he notes that the results indicated that hydroxyurea "reduced by about half the incidence of painful crises and use of blood transfusion and these very severe episodes of pneumonia-like disease that patients get." In addition, "the side effects in the short term have been minimal," Steinberg comments. But that's just the short term. "This is a drug that has a potential for other side effects, mainly carcinogenesis or leukemogenesis." Steinberg was selected to run a Phase IV follow-up study of patients taking hydroxyurea. "What we're doing is trying to see what the long-term side effects are." FDA's expected approval will cover only adult use of the drug. Clinical trials to test the safety and effectiveness of hydroxyurea in children-the patients in whom some believe it has the greatest potential for long-term benefit-are winding up now. Duane R. Bonds, leader of the sickle cell research group at the National Heart, Lung, and Blood Institute (NHLBI), expects that data from those trials should be available within three months. Even if hydroxyurea turns out to be safe for long-term use in adults and children, "it's not the last word in the chapter of treatment," Steinberg points out. "It's the first drug that does some good for the symptoms of the disease and the cause of the disease." POTENTIAL BENEFIT: Chicago's William McDade found that nitric oxide increases the solubility of sickle hemoglobin. Another potential treatment that's quite a bit further from widespread use is inhaled nitric oxide. "Nitric oxide is a pulmonary vasodilator, and my thinking originally was [that] it would be useful with people with acute chest syndrome," a pneumonia-like illness caused by occlusion of pulmonary blood vessels, explains William A. McDade, an assistant professor of anesthesiology and critical care at the University of Chicago. But further investigation by McDade and C. Alvin Head of Massachusetts General Hospital in Boston revealed two additional-and completely unexpected-potentially beneficial effects of nitric oxide. According to McDade, Head demonstrated that "sickle hemoglobin is able to give up its oxygen less avidly in the presence of nitric oxide, which means that it's more in the oxy form than the deoxy." Hence, it's less likely to sickle (C.A. Head et al., Journal of Clinical Investigation, 100[5]:1193-8, 1997). Secondly, McDade discovered that nitric oxide increases the solubility of sickle hemoglobin, making it less likely to form polymers. This work was all done in vitro, and Head is just in the beginning stages of clinical trials of inhaled nitric oxide gas, so it will be some time before it's known whether nitric oxide will be an effective remedy. But hydroxyurea, nitric oxide, and several other remedies that have been tried or proposed are treatments, not cures. A true cure for sickle cell disease is not only possible, but also a present-day reality for a small number of people. "A few patients-probably 100 or so around the world-have been cured of their sickle cell disease through bone-marrow transplantation," explains Ohene-Frempong. (Data on 22 of those patients can be found in M.C. Walters et al., New England Journal of Medicine, 335[6]:369-76, 1996.) "But as it's currently conducted, and by the criteria we currently use for transplantation, probably a little less than 5 percent of our patients will be eligible." First of all, potential recipients must have a sibling without sickle cell disease whose bone marrow is an exact immunological match. That criterion alone eliminates 85 percent of the patient population. Then, because transplants themselves carry a significant risk, the procedure is reserved for those who are severely affected by the disease and have not responded well to other treatments. "About 80 percent of those who have had transplants so far are cured and free of any transplant complications," observes Ohene-Frempong. But as Bonds remarks, the flip side of that coin is that transplants present "a 10 percent risk of death [mostly from graft vs. host disease and other complications], and in addition bone marrow transplantation results in permanent infertility, so we tell patients and their parents that they have to weigh very carefully the risks of the procedure . . . against the severity of their sickle cell disease." For years, progress in sickle cell disease was hampered by the lack of an animal model. But now that's changing. "We support several of the groups and investigators that have been looking at the transgenic mouse model of sickle cell disease," notes NHLBI's Bonds, "and there have been some very interesting reports coming out. We have our fingers crossed that that's going to allow us to try more drug therapies out first before we go onto work in humans." Last October, research groups led by Tim Townes at the University of Alabama, Birmingham (UAB) and Eddy Rubin at the Lawrence Berkeley National Laboratory announced separate transgenic mouse models of sickle cell disease in back-to-back articles in Science (T.M. Ryan et al., Science, 278:873-6, 1997; C. PØszty et al., Science, 278:876-8, 1997). As Townes, a professor of biochemistry and molecular genetics at UAB, tells it, it was a very laborious process. First they had to make mice that expressed genes for human alpha-globin and beta-globin. (A defect in the beta-globin gene causes sickle cell disease.) Then they had to knock out the mouse's own globin genes. Finally, recalls Townes, "We wanted to make animals that made human fetal hemoglobin, and we wanted them to switch at about the same time as sickle patients. Human patients are healthy when they're born, because they make 50 [percent] to 70 percent fetal hemoglobin. And then, at about three months of age, their fetal hemoglobin starts to decline and their adult hemoglobin rises, and of course their adult hemoglobin is sickle hemoglobin." This is where the two mouse models differ most significantly. The UAB mice switch from fetal to adult hemoglobin shortly after birth, while the Lawrence Berkeley mice switch before birth. Both models are likely to be highly useful. Of his mice, Townes says, "They mimic [the human disease] very accurately. In the first place, they're severely anemic. They have very low hemoglobin levels, low hematocrits, and their red cells sickle in vivo just like we see in human patients. We also see organ damage that's characteristic of sickle cell disease. [But] we're not really able to document a painful crisis in the mice." He and colleagues were expecting to send breeding pairs out to 20 or more labs last month. As to his own plans for the sickle cell mice, Townes explains, "We will concentrate on strategies for gene therapies. We've developed anti-sickling globin genes that we plan to deliver to bone marrow stem cells from these animals and transplant them back into the animals. . . . There are 10 or more strategies to test, and we just needed an animal model to test all of these." The National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/nhlbi/nhlbi.htm Sickle Cell Disease Association of America 200 Corporate Pointe, Suite 495 Culver City, Calif. 90230-7633 (800) 421-8453 Sickle Cell Information Center P.O. Box 109 Grady Memorial Hospital 80 Butler St. Atlanta, Ga. 30335 (404) 616-3572 Fax: (404) 616-5998 http://www.emory.edu/PEDS/SICKLE/ The center is jointly sponsored by the Georgia NIH Comprehensive Sickle Cell Center at Grady Health System, Atlanta; the Emory University School of Medicine, and Emory University School of Medicine, Department of Pediatrics; and the Sickle Cell Foundation of Georgia Inc. A recent review article on sickle cell disease: H.F. Bunn, "Pathogenesis and treatment of sickle cell disease," New England Journal of Medicine, 337(11):762-9, 1997. "What we do is remove bone marrow from an animal and purify hematopoietic stem cells," Townes continues. "Those are the progenitors of all blood cells. And then we would insert our anti-sickling gene-with all the right regulatory elements for high level erythroid-specific expression-into a virus that could efficiently transduce that gene into the stem cell. We would then transplant that stem cell back into the animal. . . . If we produced 15 [percent] or 20 percent anti-sickling hemoglobin and up to 85 percent sickle hemoglobin, their cells would not sickle. That's our goal-to just produce enough hemoglobin that would competitively inhibit the sickling process." But that's easier said than done. According to Townes, researchers working on gene therapy will have to try many different permutations and combinations of anti-sickling globin genes, attached regulatory elements, and schemes for incorporating these into the recipient's genome, such as retroviruses or other vectors. "And then there's the tough problem of keeping the transferred gene on long enough to be effective," he points out. "One of the major blocks to gene therapy now is the genes can be introduced into the stem cells and they are expressed relatively well at first, but then they become silenced. "There are significant hurdles to overcome," he acknowledges. "We don't want to intimate that a cure is right around the corner. I think it's going to take three or four years to overcome the technical barriers even in these animals. So I think it's five years before we could really test them [in people]." Ohene-Frempong agrees. "My own estimate is that in five years there may be some human attempts, and in probably 10 years or so there may be some ways to really manipulate the genes in this disease." But it'll be worth waiting for, he says, because "gene therapy is the ultimate cure of sickle cell disease." Funding for sickle cell research comes mostly from NHLBI, which provided $37.7 million in the 1996 fiscal year, the most recent year for which final figures are available. Ohene-Frempong believes that the funding is inadequate. "'Enough' means where we're happy with how things are at the moment, and that's not the case. We could have a lot more support for gene therapy. We could have a lot more support for drug development. And I think drug companies could show a lot more interest in research than they have so far." Ohene-Frempong thinks that race-but not necessarily racism-may play a role in the poor funding situation. "In [the United States], at least, it's a disease that affects mostly African Americans who, politically and economically, don't have much influence, and so it becomes a lower priority area. . . . I don't think people actively decide not to fund sickle cell research because it's a disease of African origin, at least in [the U.S.]. But I think there's something I call, 'It's not my cousin's disease,' that operates in sickle cell research and other research areas. If several congressmen, when they went home for the Christmas vacation, had nieces and nephews with sickle cell disease telling them how they felt, I think that when they came back to Capitol Hill they'd want to do something about it. They don't know about it, they don't hear about it, and it's not their cousin's or niece's or nephew's disease." Robert Finn, a freelance science writer based in Long Beach, Calif., can be reached online at finn@nasw.org.

Sickle Cell Treatments Improve; Genetic Cure On The Horizon

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