Sickle Cell Disease: Gene-Editing Tools Point to Possible Ultimate Cure

Posted on October 25, 2016 by Dr. Francis Collins Caption: An electron micrograph showing two red blood cells, one normal (right) and the other (left) deformed by crystalline hemoglobin into the “sickle” shape characteristic of patients with sickle cell disease. Credit: Frans Kuypers: RBClab.com, UCSF Benioff Children’s Hospital Oakland Scientists first described the sickle-shaped red blood cells that give sickle cell disease its name more than a century ago. By the 1950s, the precise molecular and genetic underpinnings of this painful and debilitating condition had become clear, making sickle cell the first “molecular disease” ever characterized. The cause is a single letter “typo” in the gene encoding oxygen-carrying hemoglobin. Red blood cells containing the defective hemoglobin become stiff, deformed, and prone to clumping. Individuals carrying one copy of the sickle mutation have sickle trait, and are generally fine. Those with two copies have sickle cell disease and face major medical challenges. Yet, despite all this progress in scientific understanding, nearly 70 years later, we still have no safe and reliable means for a cure. Recent advances in CRISPR/Cas9 gene-editing tools, which the blog has highlighted in the past, have renewed hope that it might be possible to cure sickle cell disease by correcting DNA typos in just the right set of cells. Now, in a study published in Science Translational Medicine, an NIH-funded research team has taken an encouraging step toward this goal [1]. For the first time, the scientists showed that it’s possible to correct the hemoglobin mutation in blood-forming human stem cells, taken directly from donors, at a frequency that might be sufficient to help patients. In addition, their gene-edited human stem cells persisted for 16 weeks when transplanted into mice, suggesting that [...]

BCL11A-based gene therapy for sickle cell disease passes key preclinical test

September 06, 2016 Decades-old discovery about fetal hemoglobin is on track for clinical trial in the coming year A precision-engineered gene therapy virus, inserted into blood stem cells that are then transplanted, markedly reduced sickle-induced red-cell damage in mice with sickle cell disease, researchers from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center report today in the Journal of Clinical Investigation. The work sets the stage for bringing a decades-old discovery about sickle cell disease to the bedside. A clinical gene therapy trial, using a virus rendered harmless in the laboratory, is expected to launch in the coming year. Sickle cell disease is caused by a mutation in hemoglobin, the oxygen-carrying protein in red blood cells, which causes the usually pliant cells to stiffen and assume a curved or “sickled” shape. These sickled cells live less long than those with healthy hemoglobin, leading to anemia. They also bind together, leading to a blockage of blood flow that can cause severe pain and organ damage throughout the body. The new gene therapy is the culmination of research going back to the 1980s, which found that sickle cell disease is milder in people whose red blood cells carry a fetal form of hemoglobin. Fetal hemoglobin normally tails off after birth, but in 2008, Dana-Farber/Boston Children’s researchers Stuart Orkin, MD, andVijay Sankaran, MD, PhD, showed that suppressing a gene called BCL11A — which acts as an “off” switch — could restart fetal hemoglobin production. In 2011, using this approach, they corrected sickle cell disease in mice, replacing much of the defective beta (“adult”) hemoglobin that causes sickling with healthy fetal hemoglobin. To turn this insight into a therapy, a team led by Dana-Farber/Boston Children’s researchers David A. Williams, MD, [...]

Blood-forming stem cells likely hold the key to curing many types of disease

Science Friday July 20, 2016 · 7:45 AM EDT By Adam Wernick Researchers at Stanford are reviving a technique that can use uncontaminated, blood-forming stem cells to treat a patient with cancer, autoimmune deficiency and other diseases. Beginning in the 1960s, hematopoietic, or blood-forming, stem cells became the basis for bone marrow transplants used to treat cancer patients. Then, in the 1980s and 1990s, scientists found a way to stimulate these stem cells to move from the bone marrow into the bloodstream for collection — a process called mobilization — which gradually lessened the need for bone marrow transplants. According to a 1996 study, the use of mobilized blood cells in cancer patients had multiple benefits: It led to “lower morbidity, and greater cost-effectiveness compared with conventional bone marrow transplant …and the relative ease of obtaining large amounts of stem cells made multi-cycle transplantation a viable option in the treatment of malignancies, allowing further escalation of chemotherapy dose intensity.” In 1988, Irv Weissman, a longtime stem cell researcher, developed a process that could create "purified" blood-forming stem cells from mobilized blood — that is, they could extract pure, uncomtaminated stem cells from all the other cells in the mobilized blood. This discovery became important, Weissman says, because of results found in a 1990 trial that treated women with metasticized breast cancer — cancer that has moved beyond the breast and the lymph nodes to the bones, the lung and the liver. These patients had no hope of any localized therapy to save them, but “you could give high-dose chemotherapy, and the more chemotherapy you gave the more cancer cells in the body you killed,” Weissman explains. “[But] when we looked at the mobilized blood from those women, we saw that over half of the samples [still] had breast cancer cells in [...]

Making bone marrow transplants safer

New approach would use antibodies rather than radiation and chemotherapy June 7, 2016 | Editor's Pick Popular  By Hannah L. Robbins, Harvard Stem Cell Institute B.D. Colen/Harvard Stem Cell Institute Communications Rahul Palchaudhuri (left), postdoctoral fellow, and David Scadden, co-director of the Harvard Stem Cell Institute, look at real-time images of blood stem cells settling into bone marrow. Harvard Stem Cell Institute (HSCI) scientists have taken the first steps toward developing a treatment that would make bone marrow blood stem cell transplantation safer, and as a result, more widely available to the millions of people living with blood disorders such as sickle cell anemia, thalassemia, andAIDS. Bone marrow transplantation is the only curative therapy for these blood diseases. But for the new, transplanted stem cells to do their work, faulty stem cells must first be “evicted” or killed. Accomplishing that requires patients to endure chemotherapy and radiation, a vicious assault on the body with lifelong consequences. In a study recently published in the journal Nature Biotechnology, HSCI researchers at Harvard University and Massachusetts General Hospital (MGH), in collaboration with Boston Children’s Hospital and Dana-Farber Cancer Institute, all Harvard affiliates, have developed a nontoxic transplantation procedure using antibodies to specifically target blood stem cells in mice, an approach they hope will make blood stem cell transplants for these patients far less toxic. The new treatment removes more than 98 percent of blood stem cells, making it as effective as chemotherapy and radiation, researchers said. “Instead of using non-targeted drugs that have lots of collateral damage, we thought we could take advantage of the precision of the immune system, in particular antibodies,” said David Scadden, co-director of HSCI, the Gerald and Darlene Jordan Professor of Medicine, and [...]

Calgary doctors develop new stem-cell transplant procedure to cure children with sickle cell anemia

Published on: June 6, 2016 | Last Updated: June 6, 2016 7:23 PM MDT by Alia Dharssi Cardelia Fox, centre, with her sister Tamika Allen and Dr. Greg Guilcher at the Children's Hospital on Monday June 6, 2016. Cardelia suffered from sickle cell anemia and was treated by Dr. Guilcher with stem cells from her sister Tamika. MIKE DREW / POSTMEDIA When she was just six months old, Cardelia Fox had a stroke — the first of three she would experience as a child. At the time, doctors told her parents she wouldn’t live past five because she suffered from sickle cell anemia, a genetic blood disorder in which abnormal sickle-shaped red blood cells hinder the flow of oxygen through the body. Now 19, the bubbly Calgarian of Jamaican descent is cured of the disease thanks to a new stem-cell transplant procedure being spearheaded among children by the Alberta Children’s Hospital with potentially global implications. “It’s really a breakthrough,” said Anna Banerji, a pediatrician and professor at the University of Toronto. “This could make a huge difference in the life of a child.” To date, the hospital has successfully cured sickle cell anemia in nine children with a new protocol for stem-cell transplants, which involves a bone marrow donation from a sibling who is a 100 per cent match, but does not have sickle cell anemia. The odds a patient has such a sibling are one in five. Stem-cell transplants for children and teenagers with sickle cell anemia have grown increasingly common in recent years and are carried out in many hospitals in the U.S. and Europe, said George Buchanan, professor of pediatrics at the University of Texas Southwestern Medical Centre. But Alberta Children’s approach is unique because it is likely [...]

Researcher finds novel way to monitor serious blood disorder using a smart phone

Sept. 22, 2015 Eureka Alert! Gisele Galoustian Florida Atlantic University receives NSF grant A researcher from Florida Atlantic University has come up with a unique way to monitor sickle cell disease -- a serious blood disorder -- using a smart phone. With a $166,935 grant from the National Science Foundation, E. (Sarah) Du, Ph.D., assistant professor in the Department of Ocean and Mechanical Engineering in FAU's College of Engineering and Computer Science, and principal investigator, will develop a portable smart sensor and a phone application for patients to analyze and store the results of their blood tests on a smart phone. This technology will enable them to keep a close watch on any abnormal activities in their blood cells and take important steps to manage this disease with early intervention. Sickle cell disease is a hereditary blood disorder that affects red blood cells, distorting their natural disc shape into a crescent moon or "sickle" shape. Normal red blood cells move freely through small vessels throughout the body to deliver oxygen. With sickle cell disease, the misshapen red blood cells become hard and sticky, making it difficult for them to move through blood vessels. They eventually block the flow and break apart. This process results in a number of problems including severe chronic pain, stroke, organ damage, spleen dysfunction, heart failure and even death. "A major challenge in the management of sickle cell disease is the tremendous pain that patients endure from chronic and acute pain episodes called pain crisis," said Du. "Unfortunately, these pain episodes are unpredictable and patients never know when or where these episodes will take place." Integrating microfluidics with communication technologies like a smart phone, Du and her collaborators will create a disposable [...]

Lab-produced blood cells set for human trials in landmark project involving Cambridge scientists

CambridgeNews  |  Posted: June 25, 2015 By Freya Leng NHSBT Blood Van Cambridge scientists are involved in a landmark project that will see red blood cells produced in the laboratory transfused into humans by 2017, NHS Blood and Transplant has announced. The in-man clinical trials of manufactured blood form a key part of the blood and organ service's 2020 Research and Development programme. The plan outlines how NHS Blood and Transplant, in partnership with leading universities including Cambridge, will develop transfusion, transplantation and regenerative medicine over the next five years. Dr Nick Watkins, from the University of Cambridge and NHS Blood and Transplant Assistant Director of Research and Development said: "Scientists across the globe have been investigating for a number of years how to manufacture red blood cells to offer an alternative to donated blood to treat patients. We are confident that by 2017 our team will be ready to carry out the first early phase clinical trials in human volunteers. "These trials will compare manufactured cells with donated blood. The intention is not to replace blood donation but provide specialist treatment for specific patient groups. "Research has laid the foundation for current transfusion and transplantation practices. Continued investment in research and development is critical to our role in saving and improving lives through blood and organ donation. Our five-year research and development plan will ensure we advancetreatment of all who depend upon our products and services. "The manufactured red cell trials form part of our world-leading work in regenerative medicine and one of eight research goals for 2015-2020 that will bring long-term improvements for patients and donors." Scientists from NHS Blood and Transplant and the Universities of Bristol, Cambridge and Oxford - led by Prof [...]

MGH gives grant to low-cost sickle cell diagnostic

Mar 31, 2015 Jessica Bartlett Reporter-Boston Business Journal Massachusetts General Hospital’s Center for Global Health is helping to fund an affordable sickle cell diagnostic, awarding $100,000 to the Whitesides Research Group. Courtesy/Whitesides Research Group A density test can tell whether someone has sickle cell disease. The team, led by Harvard University Chemistry Professor George Whitesides, has been working on diagnostic for years, and has a prototype that has been tested in both the lab and in Zambia. The test currently costs 50 cents a piece, though engineers are hoping to make it cheaper The money, granted through the Consortium for Affordable Medical Technologies, will help engineers perfect the prototype, as well as ensure that the prototype functions within a larger manufacturing and shipping process. “We’re at a stage where we’re hoping to have a commercial partner soon and move forward on this,” said AJ Kumar, postdoctoral fellow and Whitesides Research Group member who is leading the sickle cell disease project. The diagnostic works by filtering blood into a solution that is able to parse out cells based on their density. Sickle cells, which are deformed red blood cells shaped like a C, are denser than normal red blood cells, and sink to the bottom of the solution. “The main goal is to identify people with sickle cell disease, but even if we can help with the screening process…that could also be a win,” Kumar said. Currently, sickle cell disease affects more than 300,000 newborns every year, most in sub-Saharan Africa and India. Timely diagnosis can be difficult due to out of hospital births, a lack of reliable electricity and a shortage of trained personnel. An affordable diagnostic would help children get the care they need before they suffer [...]

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 [also] 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 “[the drug] 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. Hydroxyurea 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 [...]

Johns Hopkins researchers engineer custom blood cells

Step toward new treatment for patients with sickle cell disease March 9, 2015 JOHNS HOPKINS MEDICINE 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. [...]