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 […]

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 […]

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 […]

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 […]