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 […]
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. […]
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 […]
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, […]
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 […]
Tuesday, May 22, 2012 By: Lee Roop Dr. Tim Townes of the University of Alabama in Birmingham has been awarded the $20,000 HudsonAlpha Prize for his work on sickle cell and related blood disorders. HUNTSVILLE, Alabama — Dr. Tim Townes of the University of Alabama in Birmingham has been awarded the $20,000 HudsonAlpha Prize for his work on sickle cell and related blood disorders. The award was announced Thursday at the spring benefit of the HudsonAlpha Institute for Biotechnology in Huntsville. “In research you never speak lightly of curing a disease, but if anyone is going to cure sickle cell, it will be Tim,” said Dr. Rick Myers, director and president of HudsonAlpha. Townes, professor and chairman of the Department of Biochemistry and Molecular Biology at UAB, studies molecular genetics in red blood cells. Using mice, he and colleagues have been able to “reprogram cells that mimic sickle cell anemia as induced pluripotent stem cells,” a HudsonAlpha release said. Those cells have the potential of becoming any type of tissue. Researchers have corrected the DNA mutation associated with sickle cell, placed the cells back into donor mice and produced healthy red blood cells. He has repeated similar steps in humans up to replacing the corrected cells.
Wednesday, September 28, 2011 By: Johns Hopkins Medicine Using a patient’s own stem cells, researchers at Johns Hopkins have corrected the genetic alteration that causes sickle cell disease (SCD), a painful, disabling inherited blood disorder that affects mostly African-Americans. The corrected stem cells were coaxed into immature red blood cells in a test tube that then turned on a normal version of the gene. The research team cautions that the work, done only in the laboratory, is years away from clinical use in patients, but should provide tools for developing gene therapies for SCD and a variety of other blood disorders. In an article published online August 31 in Blood, the researchers say they are one step closer to developing a feasible cure or long-term treatment option for patients with SCD, which is caused by a single DNA letter change in the gene for adult hemoglobin, the principle protein in red blood cells needed to carry oxygen. People who inherited two copies — one from each parent — of the genetic alteration, the red blood cells are sickle-shaped, rather than round. The misshapen red blood cells clog blood vessels, leading to pain, fatigue, infections, organ damage and premature death. Although there are drugs and painkillers that control SCD symptoms, the only known cure — achieved rarely — has been bone marrow transplant. But because the vast majority of SCD patients are African-American and few African-Americans have registered in the bone marrow registry, it has been difficult to find compatible donors, says Linzhao Cheng, Ph.D., a professor of medicine and associate director for basic research in the Division of Hematology and also a member of the Johns Hopkins Institute for Cell Engineering. “We’re now one step […]
Sunday, May 23, 2010 By: Shavonne Potts Salisbury (N.C.) Post More than 80,000 U.S. residents, mainly people of African ancestry, are affected by the inherited blood disorder. Kelly Holloway reaches out for her cat, Jax, a rescued Persian with long cream-colored fur, but she’s not quite able to connect with him. It could be the mask, gloves or the hospital gown she wears over her clothes. Holloway is almost completely covered from head-to-toe. It’s the best way to protect herself and her immune system. Holloway, who grew up in Cleveland, recently underwent a procedure that she hopes will completely cure her of the inherited blood disorder, sickle cell disease. At 6 months old, Holloway was diagnosed with sickle cell, which causes red blood cells to contort and causes them to block blood vessels. “Her blood count was low and the doctors did another test,” said Alice Holloway, Kelly’s mother. That second test confirmed doctors’ suspicions that the infant had sickle cell. Sickle cell is caused by abnormal hemoglobin, a protein in red blood cells that transports oxygen and gives blood its red color. Normal red blood cells look like doughnuts without holes and move easily through the blood vessels. Sickle cells form a “C” or sickle shape and clump in the blood vessels. In the United States, more than 80,000 people are affected by sickle cell disease, mainly people of African ancestry and to a lesser extent people of Hispanic, Middle Eastern, Asian and white ancestry. Kelly, now in her 40s, is a part of a study at the National Institutes of Health in Bethesda, Md., where she’s received an experimental bone marrow transplant that researchers believe is a possible cure for sickle cell disease. […]