Sickle Cell Drug Offers “Overwhelming” Gains as “Exciting” Stem Cell Trial Starts

Mon, 03/16/2015 – 3:58pm

Cynthia Fox, Science Editor

Normal blood cells next to a sickle-blood cell, colored scanning electron microscope image (Credit: OpenStax College)A clinical trial of the most common sickle cell anemia drug, hydroxyurea, was halted a year early this winter because of “overwhelming evidence of benefit,” reported University of Nebraska Medical Center pediatric researcher Stephen Obaro, M.D., Ph.D., in The Lancet.Hydroxyurea is “the only readily available disease-modifying therapy for patients with sickle cell,” Principal Investigator Russell Ware, M.D., Ph.D., told Drug Discovery & Development, so this was good news to patients and clinicians. Ware is director of hematology at the Cincinnati Children’s Hospital.

“Recently published National Institutes of Health (NIH) evidence-based guidelines suggest it should be used more often,” Ware added.

But hydroxyurea does not solve all problems. It ultimately fails 50 percent of patients (if this number may drop with more widespread and knowledgeable use of the drug.) Average sickle cell patients only live into their 40s (if this number, too, could change with more widespread and knowledgeable use of the drug.) And while “ is widely available in the U.S. and Europe, it is not in low-resource countries,” Ware told Drug Discovery & Development. Given that two-thirds of the 305,800 newborns with sickle cell anemia live in Africa, this is one of many problems.

So other approaches are being investigated globally, including a pioneering genetically engineered stem cell clinical trial that recently enrolled its first patient.


Sickle cell anemia occurs as the result of an inherited mutation in the oxygen-carrying hemoglobin (Hbs) gene. This causes red blood cells to become sticky, and form a sickle shape, which impairs their ability to carry oxygen, and causes them to aggregate and form constant blockages in the blood stream. As red blood […]

Johns Hopkins researchers engineer custom blood cells

Step toward new treatment for patients with sickle cell disease

Researchers at Johns Hopkins have successfully corrected a genetic error in stem cells from patients with sickle cell disease, and then used those cells to grow mature red blood cells, they report. The study represents an important step toward more effectively treating certain patients with sickle cell disease who need frequent blood transfusions and currently have few options.

The results appear in an upcoming issue of the journal Stem Cells.

In sickle cell disease, a genetic variant causes patients’ blood cells to take on a crescent, or sickle, shape, rather than the typical round shape. The crescent-shaped cells are sticky and can block blood flow through vessels, often causing great pain and fatigue. Getting a transplant of blood-making bone marrow can potentially cure the disease. But for patients who either cannot tolerate the transplant procedure, or whose transplants fail, the best option may be to receive regular blood transfusions from healthy donors with matched blood types.

The problem, says Linzhao Cheng, Ph.D. , the Edythe Harris Lucas and Clara Lucas Lynn Professor of Hematology and a member of the Institute for Cell Engineering, is that over time, patients’ bodies often begin to mount an immune response against the foreign blood. “Their bodies quickly kill off the blood cells, so they have to get transfusions more and more frequently,” he says.

A solution, Cheng and his colleagues thought, could be to grow blood cells in the lab that were matched to each patient’s own genetic material and thus could evade the immune system. His research group had already devised a way to use stem cells to make human blood cells. The problem for patients with sickle […]

Investigational Therapy Could Attack Cause of Sickle Cell Crises

Mar. 2, 2015 By Duke Medicine News and Communications
DURHAM, N.C. – Treatment for painful episodes of blood vessel obstruction in sickle cell anemia is currently limited to controlling pain, but an investigational therapy might be able to interfere with the underlying cause of these events, known as vaso-occlusion crises, researchers at Duke Medicine report.
In a small, multicenter patient study led by Marilyn J. Telen, M.D., Wellcome Professor of Medicine in the division of hematology at Duke University Medical School, patients who received an investigational drug had quicker resolution of the pain episode, although the difference compared to a control group did not rise to statistical significance.

Telen said the study’s small size, as well as the wide variability in the length of time that all of the study patients suffered painful vascular obstruction, contributed to the statistical draw. A larger, international study is planned to begin later this year to provide greater clarity.

Patients who received the investigational drug also used far less pain medication, which was self-administered. Those findings were statistically significant.

The findings were reported online March 2, 2015, in the journal Blood.

“We have not had good therapies for people with this disease,” Telen said. “But this approach shows more promise than anything else I’ve seen in 34 years of treating sickle cell disease.”

Sickle cell anemia is a genetic condition in which some of the red blood cells are stiff and shaped like crescents, or sickles, rather than smooth and round. The abnormal blood cells can build up and block blood flow to limbs and organs, causing severe pain and organ damage.

The National Heart, Lung, and Blood Institute estimates that up to 100,000 people in the United States, primarily African-Americans, have the disease. The disease affects […]

Successful Outcome Brings Early End To TWITCH Sickle Cell Anemia Clinical Trial

BioNews Texas, by Charles Moore ~ December 1, 2014

Sickle cell anemia is the most common form of sickle cell disease among a group of inherited red blood cell disorders and the most common genetic disease in the U.S., afflicting an estimated 70,000-80,000 Americans according to the William E. Proudford Sickle Cell Fund Inc.

Normal red blood cells, which are shaped like doughnuts, contain an iron-rich, oxygen-carrying protein called hemoglobin, and travel easily through the body’s circulatory pathways delivering oxygen to cells. Sickle red blood cells, by contrast, become hard, sticky and shaped like sickles — crescent-shaped hand tools used to cut wheat and other crops prior to the mechanized agriculture era. As these cells hardened, pointed red cells move through small blood passageways, they clog the flow and break apart, causing pain and damage, the risk of infection, and a low blood count, or anemia. Sickle cells also contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S. Sickle hemoglobin is what causes the cells to develop their characteristic crescent shape.

Sickle cell disease affects people of many ethnicities, including people whose ancestors were from Mediterranean countries such as Greece, Turkey, and Italy; the Arabian Peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean. However, it disproportionately affects people of African descent. Approximately 1 out of 10-12 African Americans has sickle cell trait — a genetic predisposition to developing sickle cell anaemia, although not all will actually develop the disease.

According to a multi-institutional study that included researchers from The University of Texas Health Science Center at Houston (UTHealth), conclusive findings show that hydroxyurea therapy offers safe and effective disease management of sickle cell anemia and reduces the risk of stroke.

The promising data […]

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 […]

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 […]

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 […]

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 […]

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 […]

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 […]