Sickle Cell

Monthly transfusions reduce strokes in children with sickle cell anemia

Washington University in St. Louis, by Michael C. Purdy ~ August 20, 2014

Monthly blood transfusions reduce the risk of stroke in young patients with sickle cell anemia, scientists report Aug. 20 in The New England Journal of Medicine.

An estimated 1 in 3 children with sickle cell anemia experiences silent strokes — loss of blood flow to parts of the brain. Such strokes do not cause immediate symptoms and typically go undiagnosed. But damage from these incidents, which often recur, can lower a child’s IQ.

A new multi-institutional study that originated at Washington University School of Medicine in St. Louis showed that giving monthly blood transfusions to sickle cell anemia patients who already had experienced silent strokes reduced by 58 percent their risk of another stroke, silent or otherwise.

“The data make transfusion the only evidence-based option to prevent stroke recurrence and further brain injury in this vulnerable population,” said coauthor Michael Noetzel, MD, professor of neurology and of pediatrics and chair of the study’s neurology committee. “Now that we have identified a viable treatment option, early detection of silent cerebral strokes should become a major focus for clinicians and families of children with sickle cell disease.”

Noetzel treats patients with strokes from sickle cell anemia at St. Louis Children’s Hospital. He and his colleagues recommend checking children with sickle cell anemia for silent strokes at least once before they start elementary school. If an MRI scan reveals any such strokes, families and physicians should consider monthly blood transfusions.

Sickle cell anemia affects about 100,000 people in the United States and occurs most commonly in African-Americans. The disease, inherited from both parents, causes some of the patient’s red blood cells, normally shaped like a saucer, to take on a crescent or sickle shape. These malformed cells are less effective at their primary job, conveying oxygen from the lungs to the rest of the body. The cells also clump together, blocking circulation and leading to organ damage, strokes and episodes of intense pain.

Sickle-shaped blood cells break down more rapidly than normal blood cells. Researchers believe debris from these cells may clog blood vessels in the brain, causing strokes.

For the new study, scientists at Washington University and 28 other institutions screened sickle cell anemia patients to identify 196 children ages 5 to 15 who already had suffered silent strokes. The scientists gave 99 of those children monthly blood transfusions for three years. Six children went on to have additional silent or overt strokes. In contrast, in the group of 97 children who did not receive monthly transfusions, 14 had additional strokes, a difference that is statistically significant.

“We think the transfusions are helping because they raise the total amount of circulating blood and lower the percentage of sickle-shaped cells in the patient’s bloodstream,” said coauthor Allison King, MD, assistant professor of pediatrics and of occupational therapy. “Keeping the sickled cells to less than 30 percent of total blood cells seems to be ideal.”

The treatments also reduced the occurrence of sickle cell crises — the irregular attacks of acute pain that plague some patients.

Risks from the transfusions include infections, allergic reactions to the donated blood and long-term buildup of excessive iron in the bloodstream from multiple transfusions, which can damage the heart and liver.

“The risk of infection is quite low — we’re getting very good at screening our blood supply,” King said. “The risk of an allergic reaction can be reduced through better matching of compatibility factors and blood drives to increase the resources available for transfusion.”

New techniques, such as erythrocytapheresis, in which donated blood is exchanged with the patient’s sickled blood, also can help reduce the risk of iron overload, according to King.

She and her colleagues plan to conduct longer studies of children with sickle cell anemia to see whether regular blood transfusions, stem cell transplants and parenting enrichment interventions prevent declines in cognition.

Stem Cell Transplant Reverses Sickle Cell Disease in Adults

National Institutes of Health, by Staff ~ July 14, 2014

Sickle cell disease is an inherited blood disorder that affects more than 90,000 Americans, mostly of African descent. The condition arises from a genetic defect that alters the structure of hemoglobin, the oxygen-carrying protein found in red blood cells. The modified hemoglobin causes normally round red blood cells to become stiff, sticky, and sickle-shaped. The deformed cells can block blood flow, causing severe pain, organ damage, and stroke.

There is no widely available cure for sickle cell disease. Some children with the disease have been successfully treated with blood stem cell, or bone marrow, transplants. This approach, though, was thought to be too toxic for use in adults. High doses of chemotherapy are used to destroy all of a child’s bone marrow, which is then replaced with marrow from a donor. Stem cell recipients typically need to take immunosuppressants for months to a few years. These medications can cause serious side effects.

In earlier studies, transplant recipients were found to have a mix of their own and the donor’s cells in their blood. Despite the mix, sickle cell disease was reversed. Based in part on these findings in children, as well as other preliminary work, a team at NIH’s Clinical Center in Bethesda, Maryland, set out to test a modified transplant procedure in adults with sickle cell disease. The clinical trial was conducted by researchers from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Heart, Lung, and Blood Institute (NHLBI). Results appeared online on July 1, 2014, in the Journal of the American Medical Association.

Thirty patients, ages 16 to 65, with severe sickle cell disease enrolled in the study between 2004 and 2013. The patients first underwent a less toxic regimen to kill off some of their marrow cells. They then underwent a stem cell transplant, receiving cells donated by a healthy brother or sister.

The team found that the stem cell transplant reversed the disease in 26 of 30 patients (87%). The patients had normal hemoglobin, fewer hospitalizations, and lower use of narcotics to treat pain from the disease. The patients didn’t experience graft-versus-host disease—in which donor cells attack the recipient—after a median follow up of 3.4 years. Fifteen patients successfully stopped immunosuppression medications a year after the transplant. The treatment was unsuccessful in 4 patients, and some complications, such as infections, occurred.

“Side effects caused by immunosuppressants can endanger patients already weakened by years of organ damage from sickle cell disease,” says senior author Dr. John Tisdale. “Not having to permanently rely on this medication, along with use of the relatively less-toxic partial stem cell transplant, means that even older patients and those with severe sickle cell disease may be able to reverse their condition.”

The researchers continue to follow the patients to track the success of the approach. People with sickle cell disease interested in joining NIH blood stem-cell transplant studies may call 1-800-411-1222 or visit the NIH clinical trials registry at www.clinicaltrials.gov for more information.

Marrow Transplants Can Reverse Adult Sickle Cell

Bioscience Technology, by Lindsey Tanner ~ July 1, 2014

Bone marrow transplants can reverse severe sickle cell disease in adults, a small study by government scientists found, echoing results seen with a similar technique used in children.

The researchers and others say the findings show age need not be a barrier and that the technique may change practice for some adult patients when standard treatment fails.

The transplant worked in 26 of 30 adults, and 15 of them were even able to stop taking drugs that prevent rejection one year later.

“We’re very pleased,” said Dr. John Tisdale, the study’s senior author and a senior investigator at the National Institutes of Health. “This is what we hoped for.”

The treatment is a modified version of bone marrow transplants that have worked in kids. Donors are a brother or sister whose stem cell-rich bone marrow is a good match for the patient.

Tisdale said doctors have avoided trying standard transplants in adults with severe sickle cell disease because the treatment is so toxic. Children can often tolerate it because the disease typically hasn’t taken as big a toll on their bodies, he said.

The disease is debilitating and often life-shortening; patients die on average in their 40s, Tisdale said. That’s one reason why the researchers decided to try the transplants in adults, with hopes that the technique could extend their lives.

The treatment involves using chemotherapy and radiation to destroy bone marrow before replacing it with healthy donor marrow cells. In children, bone marrow is completely wiped out. In the adult study, the researchers only partially destroyed the bone marrow, requiring less donor marrow. That marrow’s healthy blood cells outlast sickle cells and eventually replace them.

Sickle cell disease is a genetic condition that damages oxygen-carrying hemoglobin in red blood cells, causing them to form abnormal, sickle shapes that can block blood flow through the veins. It can cause anemia, pain and organ damage. The disease affects about 100,000 Americans, mostly blacks, and millions worldwide.

Results from the adult study, involving patients aged 29 on average, were published Tuesday in the Journal of the American Medical Association. The usual treatment hadn’t worked, a drug called hydroxyurea, and they had transplants at an NIH research hospital in Bethesda, Maryland.

The treatment failed to reverse sickle cell in four of the 30 patients and one died of a disease-related complication. Another patient died suddenly a few weeks ago — an elderly man whose transplant four years ago had been a success. Tisdale said that man had lived longer than the normal lifespan for sickle cell patients but that his death was unexpected and an autopsy was to be performed.

The researchers are unsure why the technique didn’t work for everyone but they note that most patients survived more than three years on average, and some patients from an early phase of the study have been off anti-rejection drugs for more than seven years.

Tisdale said based on the latest results, adults with severe disease should be offered transplants if drug treatment doesn’t work. One limitation is that fewer than 1 out of 4 adults with sickle cell disease likely have siblings who would be a good match. But Tisdale said NIH scientists are studying whether relatives who aren’t as close a match would also be suitable donors.

A JAMA editorial by blood specialists at Washington University in St. Louis said the study shows that limiting the transplants to children should be reconsidered.

“These findings offer hope,” Drs. Allison King and John DiPersio wrote in the editorial.

SLU Researchers Study Therapy to Relieve Sickle Cell Pain

Newswise, by Staff ~ 1/22/14

Saint Louis University researchers are studying whether ReoPro® (abciximab), a drug currently given to heart patients undergoing angioplasties to open blocked arteries, also could help children and young adults who have severe pain from sickle cell disease.

“Sickle cell crises, which are acute episodes that can land patients in the hospital, can be excruciatingly painful,” said William Ferguson, M.D., director of the division of pediatric hematology and oncology at Saint Louis University and a SLUCare pediatrician at SSM Cardinal Glennon Children’s Medical Center.

“The typical vaso-occlusive crisis puts patients in the hospital for three to five days on intravenous medications. All we can do is give supportive care, such as pain killers, and wait for the crisis to run its course. Our research will tell us if using a medicine like ReoPro could be a valuable strategy in treating a sickle cell crisis.”

Sickle cell crises occur when clots form in the small blood vessels, preventing blood from flowing freely to organs. Healthy red blood cells are shaped like flexible donuts and can fold to easily wiggle through the smallest blood vessels. Red blood cells in patients who have sickle cell disease are misshaped, crescent-like cells with sharp edges that get caught inside blood vessel walls and pile up to create blockages.

Much like an accident that impedes traffic on the road where it happened and on secondary feeder roads, sickle cell crises cause a second blood vessel blockage when red blood cells and platelets (small blood cells that stop bleeding) stick to the lining of the blood vessel walls.

“It’s like there’s a traffic accident and a quarter mile down the road, you slow down again. Right now, we don’t have anything that directly targets that secondary blockage,” Ferguson said. “These traffic pile ups can decrease blood flow and can damage the organ on the other side, such as the spleen, eyes or lungs.”

Ferguson, who is the study chair, said the research could represent a new approach to treating sickle cell crisis. He is leading a study that examines whether or not ReoPro could reduce the length of time patients who are having a sickle cell pain crisis spend in the hospital.

“As far as I know, no one has targeted the increased stickiness of both platelets and red blood cells in the context of a crisis,” Ferguson said. “We hope our research will tell us more about treating the disease and potentially open an avenue of research and drug development.”

Scientists from SLU’s Center for World Health and Medicine reviewed medical literature that identified the mechanism of action used by ReoPro as potentially promising in treating sickle cell crises because it attacks blockages in blood flow on two fronts. They then approached Ferguson about conducting the research, said Peter Ruminski, executive director of the center.

“ReoPro hits both of those proteins that affect the stickiness of platelets and the flow of red blood cells through the walls of the blood vessels. Our research will help us find out if medications that have similar properties can be effective against sickle cell disease,” Ruminski said.

“Sickle cell disease is a neglected disease that dramatically affects members of the St. Louis community who are African American. It is devastating for those who have it in terms of diminished quality of life and shortened lifespan.”

The Center for World Health and Medicine brokered the research project, which is the first clinical trial to come out of its work. While ReoPro has been approved by the Food and Drug Administration to prevent clotting during angioplasty procedures, it has not been studied as a treatment for sickle cell disease. Janssen Biotech, Inc., the company that discovered and developed ReoPro, is donating the medication and providing funding for the study.

Ferguson is recruiting 100 patients who are between ages 5 and 25 for the double-blind randomized trial. Within 16 hours of being hospitalized for a sickle cell pain crisis, half will receive the investigational medicine and half a placebo. All will receive the standard of care, which includes pain medication, while they are in the hospital and released.

Researchers will track how long the volunteers remain in the hospital. Those in the study will be discharged from the hospital once their pain can be controlled by oral medications, provided they have no other medical problems. They will have a follow up visit with their hematologist a week to 10 days after leaving the hospital, which is routine care for those who have suffered a sickle cell crisis.

Sickle cell disease occurs in about one in 400 people of African descent and one in 4,000 Hispanics, affecting between 80,000 and 100,000 Americans. It varies in severity, with some people having significant pain from multiple crises. Typically, those who have sickle cell disease live to be in their 50s.

For some patients, the disease also interferes with the quality of life, Ferguson said.

“If you’re having multiple pain crises and going into the hospital many times a year, it’s hard to go to school or keep a job,” Ferguson said. “In addition, many people have moderate or minor crises in between hospitalizations and take narcotics to relieve the pain. That can compromise a person’s ability to function as well.”

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: infectious disease, liver disease, cancer, heart/lung disease, and aging and brain disorders. The Center for World Health and Medicine is dedicated to developing therapies for rare (orphan) and neglected diseases.

To learn more about the sickle cell disease research at Saint Louis University, call (314) 577-5638.

Studies uncover new insights into pathophysiology of sickle cell disease and thalassemia, may help improve standard of care

Medical News Today, by Staff ~ December 11, 2013

New research presented during the 55th American Society of Hematology Annual Meeting and Exposition in New Orleans uncovers several important insights into the pathophysiology of sickle cell disease and thalassemia that may soon translate into the development of better, more targeted treatments for hundreds of thousands of patients worldwide.

Sickle cell disease (SCD) is an inherited, chronic disorder affecting nearly 100,000 Americans. Instead of producing healthy red blood cells, individuals with the disease produce abnormal hemoglobin, a protein that attaches to oxygen in the lungs and carries it to all parts of the body. This abnormal hemoglobin causes the red blood cells to become rigid and sickle-shaped, which then block blood and oxygen flow to the body and lead to intense pain and infections. Thalassemia, the name for a family of chronic blood disorders characterized by low hemoglobin production, also affects the blood’s ability to transport oxygen and is associated with life-threatening complications.

While there are several ways to treat SCD and thalassemia, these options only manage symptoms and do not correct the underlying genetic defects associated with these disorders. Fortunately, investigators continue to uncover important insights related to the pathophysiology of these blood disorders and their symptoms, fueling the development of new targeted interventions that may lead to improved treatments. Findings presented today explore a promising potential pain management treatment for SCD patients as well as two strategies that use natural proteins to activate the gene responsible for the production of healthy hemoglobin.

“We now know a great deal about the causes of sickle cell disease and thalassemia and how to treat many of the complications; however, new insights and care strategies that can allow for better management of these diseases are desperately needed,” said John Tisdale, MD, moderator of the press conference and Senior Investigator of the Molecular, Clinical, and Hematology branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health in Bethesda, Md. “Exciting new developments being reported today include a new therapy that could help sickle cell patients better manage pain crises and two new gene therapy strategies that could allow patients with both sickle cell disease and thalassemia to produce healthy hemoglobin. These advances bring us one step closer to achieving our goal of improving the long-term outlook and enhancing the quality of life of patients with these serious disorders.”

GMI 1070: Reduction in Time to Resolution of Vaso-Occlusive Crisis and Decreased Opioid Use in a Prospective, Randomized, Multi-Center Double Blind, Adaptive Phase II Study in Sickle Cell Disease [776]

Vaso-occlusive crisis (VOC) is a common and painful complication of sickle cell disease (SCD) that occurs when sickled red blood cells and white blood cells stick to the lining of blood vessels, blocking blood flow and preventing oxygen from reaching parts of the body. Sickle cell patients experiencing VOC typically receive potent drugs to alleviate intense pain, but these medications only manage the symptoms and do not attack the root cause of the crisis. Previous research has suggested that molecules called selectins involved in cell-to-cell adhesion may be a significant driver of VOC. Recent studies of a new selectin inhibitor compound GM 1070 in animals have demonstrated efficacy in reducing VOC in that model system.

Newly Discovered Gene Regulator Could Precisely Target Sickle Cell Disease

Regenerative Medicine, by Staff ~ November 11, 2013

“Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.” –Dr. Stuart Orkin.

A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates hemoglobin production.

The researchers — led by Daniel Bauer, MD, PhD, and Stuart Orkin, MD, of Dana-Farber/Boston Children’s — reported their findings recently.

Prior work by Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce fetal hemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle hemoglobin. BCL11A is thus an attractive target for treating SCD.

The disease affects roughly 90,000 to 100,000 people in the United States and millions worldwide.

However, BCL11A plays important roles in other cell types, including the immune system’s antibody-producing B cells, which raises concerns that targeting it directly in sickle cell patients could have unwanted consequences.

The discovery of this enhancer — which regulates BCL11A only in red blood cells — opens the door to targeting BCL11A in a more precise manner. Approaches that disable the enhancer would have the same end result of turning on fetal hemoglobin in red blood cells due to loss of BCL11A, but without off-target effects in other cell types.

The findings were spurred by the observation that some patients with SCD spontaneously produce higher levels of fetal hemoglobin and enjoy an improved prognosis. The researchers found that these individuals possess naturally occurring beneficial mutations that function to weaken the enhancer, turning BCL11A’s activity down and allowing red blood cells to manufacture some fetal hemoglobin.

“This finding gives us a very specific target for sickle cell disease therapies,” said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. “Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.”

“This is a very exciting study,” said Feng Zhang, PhD, a molecular biologist and specialist in genome engineering at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, who was not involved in the study. “The findings suggest a potential new approach to treating sickle cell disease and related diseases, one that relies on nucleases to remove this regulatory region, rather than adding an exogenous gene as in classic gene therapy.”

UCLA Stem Cell Therapy for Sickle Cell Disease Advances Toward Clinical Trials

Newswise, by Staff ~ July 1, 2013

Researchers at UCLA’s Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research have successfully established the foundation for using hematopoietic (blood-producing) stem cells (HSC) from the bone marrow of patients with sickle cell disease (SCD) to treat the disease. The study was led by Dr. Donald Kohn, professor of pediatrics and microbiology, immunology and molecular genetics in the life sciences.

Kohn introduced an anti-sickling gene into the HSC to capitalize on the self-renewing potential of stem cells and create a continual source of healthy red blood cells that do not sickle. The breakthrough gene therapy technique for sickle cell disease is scheduled to begin clinical trials by early 2014. The study was published online ahead of press today in Journal of Clinical Investigation.

Gene Therapy

Kohn’s gene therapy approach using HSC from patient’s own blood is a revolutionary alternative to current SCD treatments as it creates a self-renewing normal blood cell by inserting a gene that has anti-sickling properties into HSC. This approach also does not rely on the identification of a matched donor, thus avoiding the risk of rejection of donor cells. The anti-sickling HSC will be transplanted back into the patient’s bone marrow and multiplies the corrected cells that make red blood cells without sickling.

“The results demonstrate that our technique of lentiviral transduction is capable of efficient transfer and consistent expression of an effective anti-sickling beta-globin gene in human SCD bone marrow progenitor cells, which improved the physiologic parameters of the resulting red blood cells.” Kohn said.

Kohn and colleagues found that in the laboratory the HSC produced new non-sickled blood cells at a rate sufficient for significant clinical improvement for patients. The new blood cells survive longer than sickled cells, which could also improve treatment outcomes. The success of this technique will allow Kohn to begin clinical trials in patients with SCD by early next year.

Sickle Cell Disease

Affecting more than 90,000 patients in the US, SCD mostly affects people of Sub-Saharan African descent. It is caused by an inherited mutation in the beta-globin gene that makes red blood cells change from their normal shape, which is round and pliable (like a plastic bag filled with corn oil), into a rigid sickle-shaped cell (like a corn flake). Normal red blood cells are able to pass easily through the tiniest blood vessels, called capillaries, carrying oxygen to organs such as the lungs, liver and kidneys. But due to their rigid structure, sickled blood cells get stuck in the capillaries and deprive the organs of oxygen, which causes organ dysfunction and failure.

Current treatments include transplanting patients with donor HSC, which is a potential cure for SCD, but due to the serious risks of rejection, only a small number of patients have undergone this procedure and it is usually restricted to children with severe symptoms.

CIRM Disease Team Program

This study was supported in part by a Disease Team I Award from the California Institute for Regenerative Medicine (CIRM), the state’s stem cell research agency created by voter initiative in 2004. The purpose of the disease team program is to support research focused on one particular disease that leads to the filing of an investigational new drug application with the FDA within four years. The program is designed to encourage translational research, which means to take scientific discoveries from the laboratory to the patient bedside as quickly as possible. This requires new levels of collaboration between basic laboratory scientists, medical clinicians, biotechnology experts and pharmacology experts, to name a few.

Other support came from the UCLA Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center and the Ruth L. Kirschstein National Research Service Award.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu

Sickle cell drug begins Phase 2 trials

U~T San Diego, by Bradley J. Fikes ~ June 16, 2013

A new approach to reducing sickle cell anemia’s painful attacks has entered Phase II clinical trials.

The drug, Lexiscan, is already approved for diagnosing heart disease. Scientists led by Joel Linden, a researcher at the La Jolla Institute for Allergy & Immunology, discovered that the drug might also be useful for relieving the attacks sickle cell patients periodically suffer.
photoNormal red blood cells take a circular shape, while sickle cells take bent, angular shapes that cause them to clump in capillaries, cutting off the flow of blood to tissues. — Betty Pace
Patients are now being recruited for the Lexiscan study, to be conducted in Boston, Baltimore, Detroit, Chicago, Cincinnati, Milwaukee, Chapel Hill, and St. Louis. Dana-Farber Cancer Institute in Boston is the sponsor; the La Jolla Institute is a collaborator. Linden is the study’s co-lead investigator with David G. Nathan, of Dana-Farber (the “dean of hematology,” Linden calls him) and Joshua Field of BloodCenter of Wisconsin.

The trial is funded by a $10.8 million grant from the National Institutes of Health.

Lexiscan has an anti-inflammatory effect, and the trial is to study whether the drug can reduce inflammation and pain during an attack, helping restore blood flow. Research has suggested that sickle cell anemia is not merely the result of deformed red blood cells; inflammation is also involved.

A molecular disease

Separately, San Diego-based HemaQuest said it has finished recruiting sickle-cell patients for a Phase 2b trial of its drug, HQK-1001. That drug, HQK-1001, induces production of fetal hemoglobin, which appears to compensate for the abnormal hemoglobin in sickle cell anemia. It has received orphan drug designation for both sickle cell disease and beta thalassemia in both the United States and Europe.

HemaQuest moved its headquarters from Seattle to San Diego in 2011. It was founded in 2007 in Newton, Mass.

Sickle cell disease is caused by a mutation in hemoglobin, the oxygen-carrying protein in red blood cells. It makes the cells curve in a characteristic sharply curved shape, instead of the normal doughnut shape. The angular lines of these cells cause them to clump in capillaries, cutting off the flow of blood, called ischemia, and starting a cascade of damage.

The disease mainly occurs in people with ancestry from certain parts of sub-Saharan Africa and the Middle East where malaria has been endemic. Those who carry one gene for the mutant hemoglobin are healthy and partially protected from malaria, but those with two genes get the disease. In the United States, the disease is most common in African-Americans.

There are various types of sickle cell disease, some occurring in conjunction with another harmful mutation that causes beta thalassemia. The sickle cell mutation was reported in the November, 1949 issue of Science by researchers including Linus Pauling. It was the first description of a molecular disease.

Linden has studied the ischemic process for years; he specializes in the effects of adenosine, a breakdown element of ATP whose levels are increased by ischemia. (San Diego history note: Gensia, a company once based in San Diego, unsuccessfully tested adenosine-regulating drugs for cardiac uses. It moved to Irvine, changed its name to Gensia Sicor and entered the generics business. The company was later purchased by Israeli pharmaceutical company Teva.)
Heart attack is ischemia in the coronary arteries. It is often treated by installing stents to restore blood flow. But damage can continue even then, Linden said.

“During the period of tissue ischemia, some of those tissues have been damaged,” Linden said. “They’re hypoxic, they’re not getting any nutrients, and when blood starts flowing into those little blood vessels, the white cells become adherent and they literally clog up the microvessels. So you go initially from a vessel that’s clogged with atherosclerosis or a clot, you open that up, and you end up with a secondary clogging. Except now, it’s in the tiny blood vessels that are downstream.”

Cardiologists call this the “no reflow” phenomenon Linden said.

“They’ll balloon open an artery, blood will start to flow, and then it will stop again,” Linden said.

Linden and colleagues studying no-reflow found that drugs activating adenosine receptors on the NKT white blood cells turned off their adherent effect, and could block the reperfusion injury.

“We found that there was an inflammatory cascade initiated by the activation of these cells and then you ended up activating a whole bunch of white cells, including neutrophils, which are abundant, and these would actually clog up the arterioles and venules,” Linden said.

Sickle cell connection

Linden says he made the link between reperfusion injury and sickle cell anemia while reading a journal about the disease.

“There are two things I read: One is that sickle-cell anemia is associated with vaso-occusion, multi-tissue, widely disseminated. The other thing is that patients who have this disease have white-cell activation,” Linden said. “So I thought, geez, this sounds just like ischemia reperfusion injury, in fact it probably is ischemia reperfusion injury. These red cells are basically creating vaso-occlusion, just like you have in coronary artery disease, except that instead of it being caused by a lipid plaque or a clot, it’s caused by red cells that are occluding the micro-vasculature.”

Linden and colleagues experimented on transgenic mice that had been given the mutated human hemoglobin gene, causing the mice to make sickle-shaped red blood cells. The mice were then treated to remove the white blood cells that cause the inflammation. They got much better, although still ill, Linden said.

“What we figured out we were doing is we were blocking the white cell activation,” he said. And that led to a different view of sickle-cell anemia than the classic model.

“Instead of thinking of sickle cell anemia just as a disease of red cells, the new concept was, it’s a combination of red cells and white cells,” Linden said. “Red cells cause the initial injury, then you get ischemia, and then you generate factors that activate these NKT cells and other white cells, and you get a multi-cellular aggregate that clogs up the arteries.”

This change in thinking was exemplified by an Aug. 1, 2000 article in the Journal of Clinical Investigation reporting that reperfusion injury occurred in the transgenic sickle cell mice but not in normal mice. Linden and colleagues then found the mechanism that caused the NKT cells to start the process.

A company called NKT Therapeutics is conducting a Phase I clinical trial of a monoclonal antibody that depletes the NKT cells in patients with stable sickle cell disease.

“The hope is they’ll get long-term protection without getting too much immunosuppression,” Linden said.

Temporary halt

However, Linden said it’s better not to deplete white blood cells, to preserve their infection-fighting power. His group’s approach is to temporarily turn off the cells’ ability to aggregate, by administering a drug during a crisis.

“It turns out adenosine receptors on these T cells turn them off,” Linden said. “So we thought all we need to do is treat with adenosine, or synthetic adenosine analogs that activate this particular receptor, and that’s going to turn off these cells.”

Linden and colleagues then looked for such adenosine analogs. They found one in Lexiscan, which was already approved for pharmacological stress-testing for heart disease. Lexiscan opens up coronary arteries, similar to what exercise would do. It’s given for patients who aren’t able to safely exercise for a stress test.

Lexiscan is injected rapidly for stress-testing; for sickle cell patients it is given as an infusion of up to 48 hours. The safety of this approach was successfully tested in a Phase I study. Linden’s role is to analyze the white cells for activation.

“As a secondary endpoint, we took blood from these patients and looked at the NKT cell activation markers,” Linden said. “We found out that in sickle cell disease they were really activated, which is exactly what we saw in the mice. And when we gave them the adenosine compound the activation was inhibited.”

Asked why there were no trial sites in California, Linden said part of the issue is finding sites that not only have large numbers of sickle cell patients, but also research programs suited to the study.

Bone marrow transplants offer cure for sickle cell patients

Sunday, July 8, 2012

By: Sandra Jordan

Little Gabby Carter of Cape Girardeau, Missouri thought going to the hospital all the time, frequent bouts of pain, staying inside during temperature extremes and fatigue were just a normal part of life. That is, until she started kindergarten.”Kindergarteners have a lot of recesses and they do a lot of things that she couldn’t do,” Debbie Carter, Gabby’s mother, said. “She got tired a lot with the activities that they do; she just couldn’t keep up and so she’d have to take frequent naps.”Gabby is one of the patients at St. Louis Children’s Hospital with sickle cell disease who are or will become stem cell or the bone marrow transplant recipients this summer.

“We have three that are in right now; we have one that has already had her transplant and is in the early phase of recovery,” Dr. Monica Hulbert, director of the Sickle Cell Disease Program at St. Louis Children’s Hospital and assistant professor of pediatrics Washington University St. Louis.

Sickle cell disease is an inherited blood disorder affecting millions of people of color around the globe. Varying types of sickle cell diseases are commonly found among African, Indian, Mediterranean, Middle-eastern, Caribbean and Latin populations.

With sickle cell disease, red blood cells produce abnormal hemoglobin, a protein that carries oxygen throughout the body and takes carbon dioxide to the lungs to breathe out. Normally rounded red blood cells are crescent or sickle shaped, reducing their ability to transport oxygen throughout the body. The sickled cells can group together and clog pathways in the bloodstream, causing painful attacks, known as episodes or crises. The disease can damage vital organs and cause strokes and premature death.

In Missouri, it is estimated one in 400 African Americans have the disease and one in 12 have the sickle cell trait, which can be passed to their children.  If both parents have the sickle cell trait, there is a one in four chance their child will also have sickle cell anemia.

Hulbert’s colleague, Dr. Shalini Shenoy, associate director of the bone marrow transplant program, has developed and is chair of several national studies to figure out ways to make bone marrow transplants available for more patients and with less side effects.

“It’s really a great opportunity to kind of see that unfold and we have multiple patients coming into the transplant unit this summer for hopefully what will be curative treatment for their sickle cell disease,” Hulbert said.

As exciting as that is for the patients, their families and their health care team, many other children need a bone marrow match.

“We have 15 or 20 kids that are waiting with no donors,” Hulbert said.

To become a bone marrow donor, persons need to sign up through BeTheMatch.org to get tested.

“To register to be a donor it requires just having a condensed swab of your cheek and filling out a bunch of forms and you could be called at any time if there was somebody who matched you – to be willing to donate for any person that you may not know, and you won’t know, most likely,” Hulbert said.

People are more likely to match somebody who is more genetically like them, making it more difficult to find acceptable matches for African Americans and any person of color, she said.

“There are not as many people of color signed up to be donors,” Hulbert said. “And that’s true not just for sickle cell disease but for other diseases that can affect anybody – like leukemia, aplastic anemia or bone marrow failure. We really need people to register to be donors for any patient that may need a bone marrow transplant.”

The hospital is also working with the St. Louis Cord Blood Bank to try and identify ways to improve cord blood donations from women of color after their babies are born.

“The cord blood contains a lot of the elements we need that are called stem cells, which can actually kind of repopulate somebody’s bone marrow and those can be what we call an alternative source instead of a bone marrow donor,” Hulbert said.  “Cord blood can be for somebody to have a transplant for sickle cell or any other similar blood disease.”

After going on the bone marrow transplant list in March 2011, two matching bone marrow donors did not work out – one because of medical reasons and the other donor just backed out. Gabby’s mother said she didn’t have time to become angry or bitter. The medical team pursued and found another option – a cord blood match for a stem cell transplant.

Gabby underwent two rounds of chemotherapy at Children’s before having a cord blood stem cell transplant on July 3.

The National Institutes of Health researchers have also reported successful results in the U.S. with stem cell transplants to adult sickle cell patients, although risks for rejection are higher with age and after experiencing major sickle cell complications.

Children’s will have an informational booth at the upcoming Sickle Cell Stroll, which takes place Saturday, July 28 at 9 a.m. in the Upper Muny Parking Lot in Forest Park in St. Louis. To register or for more information, call 314-277-3950, emailrbritts@sicklecellassociation.org or visit sicklecellstroll.com.

Chicago Woman Cured of Sickle Cell Disease

Tuesday, June 19, 2012

By: University of Illinois at Chicago

ScienceDaily (June 18, 2012) — Chicagoan Ieshea Thomas is the first Midwest patient to receive a successful stem cell transplant to cure her sickle cell disease without chemotherapy in preparation for the transplant. University of Illinois Hospital & Health Sciences System physicians performed the procedure using medication to suppress her immune system and one small dose of total body radiation right before the transplant.

The transplant technique is relatively uncommon and is a much more tolerable treatment for patients with aggressive sickle cell disease who often have underlying organ disease and other complications, says Dr. Damiano Rondelli, professor of medicine at UIC, who performed Thomas’s transplant.

The procedure initially allows a patient’s own bone marrow to coexist with that of the donor. Since the patient’s bone marrow is not completely destroyed by chemotherapy or radiation prior to transplant, part of the immune defense survives, lessening the risk of infection. The goal is for the transplanted stem cells to gradually take over the bone marrow’s role to produce red blood cells — normal, healthy ones.

Thomas, 33, had her first sickle cell crisis when she was just 8 months old. Her disease became progressively worse as an adult, particularly after the birth of her daughter. She has spent most of her adult life in and out of hospitals with severe pain and has relied on repeated red blood cell transfusions. Her sickle cell disease also caused bone damage requiring two hip replacements.

“I just want to be at home with my daughter every day and every night,” said Thomas, who depends on family to help care for her daughter during her frequent hospitalizations.

This type of stem cell transplant is only possible for patients who have a healthy sibling who is a compatible donor.

Thomas’ sister was a match and agreed to donate blood stem cells through a process called leukapheresis. Several days prior to leukapheresis, Thomas’ sister was given drugs to increase the number of stem cells released into the bloodstream. Her blood was then processed through a machine that collects white cells, including stem cells. The stem cells were frozen until the transplant.

Last Nov. 23, four bags of frozen stem cells were delivered to the hospital’s blood and marrow transplant unit. One by one, the bags were thawed and hung on an IV pole for infusion into Thomas. The procedure took approximately one hour. Her 13-year-old daughter, Miayatha, was at her bedside.

Six months after the transplant, Thomas is cured of sickle cell disease and no longer requires blood transfusions.

“The donor cells have taken over completely, and blood tests show no sickle cell disease,” said Rondelli, director of the blood and marrow transplant program at UI Hospital. Thomas continues to take medication to prevent rejection of the donor stem cells.

About 25 adults have received a similar chemotherapy-free stem cell transplant for sickle cell disease in recent years at the National Institutes of Health in Bethesda, Md. Approximately 85 percent have been cured.

“Sickle cell disease is devastating — both emotionally and physically,” said Dr. Dennis Levinson, a private rheumatologist in Chicago and clinical associate professor of medicine at UIC, who has taken care of Thomas for the past 16 years. “I’ve been terribly frustrated with Ieshea’s disease over the years, and I’ve cared for many other sickle cell patients who have died.”

Levinson says the stem cell transplant provides new hope for patients who often live day-to-day on painkillers and who are often misunderstood by clinicians. As the former chief of medicine at the now closed Michael Reese Hospital, he said he has cared for many patients with sickle cell anemia and was determined to seek out the best treatment option for Thomas.

Sickle cell disease primarily affects people of African descent. It is an inherited defect of the red blood cells that causes them to be shaped like a crescent, or sickle. These abnormal cells deliver less oxygen to the body’s tissues and can result in severe pain, stroke and organ damage.

Approximately one in every 500 African Americans born in the U.S. has sickle cell disease. The disease affects 80,000 Americans of different ethnic backgrounds.