Researcher Building Foundation for Widely Available Cure for Sickle Cell Disease

For many people living with sickle cell disease, the latest news coming from the fronts of research may be cause for serious hope. Just last year, scientists announced that an experimental gene therapy procedure appears to have eliminated the disease in a French teenager.  The Food and Drug Administration (FDA), meanwhile, recently approved the first new sickle cell drug in 20 years—Endari—which reduces pain and other complications caused by the inherited blood disorder. And a small, but growing number of sickle cell patients have been experiencing dramatic results from bone marrow transplants that, in effect, have wiped out their disease.

Now, a team of researchers at the National Institutes of Health, including NHLBI’s John Tisdale, M.D., are working to open the door to a therapy that does what no other has done: reverse sickle cell disease in much larger numbers of patients.

Tisdale, a senior investigator in the NHLBI’s Sickle Cell Branch, is leading a multi-center nationwide study to test the effects of an experimental gene therapy much like the one that ‘cured’ the patient in France. To date, 10 patients have undergone the gene therapy procedure in the United States, including three recipients at the NIH Clinical Center on the Bethesda, Maryland campus where Tisdale’s lab is located. The results are not yet available, although researchers are optimistic.

“Years of careful studies in developing genetic treatments for sickle cell disease have now matured in a way that predicts ultimate success in the clinic,” Tisdale said. He noted that NIH’s gene therapy sickle cell protocol is currently recruiting patients.

The procedure involves removing part of the patient’s bone marrow and then adding a gene for beta globulin, which is defective in sickle cell disease. The genetic mutation causes red blood cells to form a sickle shape and clump together, causing severe pain as they become stuck in the blood vessels. Left untreated, the condition can cause stroke, organ failure, and even death. Researchers hope the gene replacement will enable the bone marrow to produce normal red blood cells consistently. If it works, more patients could be treated in the future, researchers say.

“We look forward to evaluating the results in our ongoing gene therapy clinical trial,” Tisdale said. “And we’re hopeful that through this work, we can make potentially curative therapies available for many more individuals with this devastating disease.”

For now, only a handful of patients will get gene transplants for sickle cell disease as researchers conduct the clinical trials.  For others, bone marrow transplants may be an appealing option. 

Tisdale and his research team have helped develop and refine a procedure in which a person’s bone marrow is removed and replaced with bone marrow from a healthy, compatible donor who does not have sickle cell disease. While children with sickle cell disease tend to tolerate these transplants better than adults, Tisdale and colleagues have pioneered a way to successfully deliver bone marrow transplants to adults with sickle cell disease in a way that is less toxic to the body than previous techniques. The approach is particularly promising for sicker adult patients with sickle cell disease, researchers say.

At least 68 patients with sickle cell disease have undergone an experimental bone marrow transplant at NIH—worldwide, about 1,200 (mostly children). Many of the transplants have been successful to date, with nearly 90 percent success rate. Researchers are exploring ways to increase the success rate in the future. For some adult patients with the disease, the results have been life-changing (See stories on Afia Donkor and Jennifer Nsenkyire).

But Tisdale points out that not all the patients undergoing a bone marrow transplant experience a positive result. And the procedure is not available to everyone, as doctors have difficulty finding compatible donors for most patients.

Soon, more people will learn about the steady progress in sickle cell disease research. Tisdale and other NIH colleagues will be featured in First in Human, a three-part television documentary produced by the Discovery Channel that focuses on the real-life experiences of patients, researchers, and doctors at the NIH Clinical Center, which is the nation’s largest hospital devoted to clinical research. Segments will include Tisdale’s research on bone marrow transplantation for patients with sickle cell disease.

Tisdale admits that it has been a slow journey in the quest to cure sickle cell disease. He recalled how life was for patients during his internal medicine residency at Vanderbilt Medical Center more than 20 years ago.  “I saw a number with sickle cell disease coming in and out, and it just seemed like there was nothing,” he said. “We weren’t doing anything except giving pain medications. And the patients were coming right back because we weren’t doing anything to alter their disease course.” The idea that a bone marrow transplant could fix that “made a lot of sense,” he added. “I understood the limitations, but didn’t understand them to be insurmountable.”

Patient recruitment and clinical trials:

• Sickle cell studies: https://www.nhlbi.nih.gov/studies/nhlbi-trials/sickle-cell-anemia
• Clinical trials (general): https://clinicaltrials.gov/