Listen to John Tisdale discuss their work:
Two scientists at the National Institutes of Health have done pioneering sickle cell disease research over several decades, with dogged persistence, leading to a number of important advances. A recent breakthrough now appears to offer a cure that could ease the pain of millions of people worldwide who live with this progressively debilitating and life-threatening illness.
Dr. Griffin Rodgers, NIH’s godfather of sickle cell disease research, and Dr. John Tisdale, a long-time NIH associate, have pursued multiple avenues for treatment and cures, both on their own and together, and their work has led to therapies that have improved many lives.
The latest success, from a small trial Tisdale is doing with a biotech company, could make a gene therapy treatment available to a wider swath of people who live with this inherited disorder.
“Griff and John were the two people who contributed enormously to both the concept of being able to [fix the defect], and now the actual practice of using gene therapy to treat sickle cell disease,” said Dr. Michael Gottesman, deputy director for intramural research at NIH. “We really think we’ve corrected the defect.”
The hallmark of the disease is the presence of sickle-shaped red blood cells caused by a gene mutation, which can restrict blood flow and lead to severe, chronic pain, organ damage and premature death. It affects about 100,000 Americans—predominantly African Americans and, to a lesser extent, Hispanic Americans—as well as millions of people worldwide.
The most recent NIH-connected results come from Tisdale’s experimental trial with the company bluebirdbio, in which nine patients underwent gene therapy that so far seems to offer a cure.
Tisdale has “applied the newest tools in the gene therapy toolbox to provide dramatic responses, possibly even cures, for patients who have suffered for many years,” said NIH Director Francis Collins.
As more time passes after the therapy, the blood of these patients appears more like that of a sickle cell disease carrier rather than someone with the illness. The blood of the first patient in the current cohort, treated more than 21 months ago, is closer to that of someone who is disease-free.
The therapy involves taking a patient’s bone marrow, correcting a misspelled gene, and using a viral vector—a tool to deliver genetic material into a cell—as a type of Trojan horse that delivers the corrected genetic material to the patient’s bone marrow, Tisdale said.
It is one of three methods scientists in the field are using to modify stem cells to treat sickle cell disease, and it is the furthest along. Another method involves blocking a gene to prevent blood cells from sickling. The third involves editing genes with a tool called CRISPR-Cas, a method Tisdale and Rodgers are working on as well.
Tisdale’s branch also works on “half-matched” transplants using the stem cells from patients’ family members—which partially match the patient’s tissue type and are available to nearly everyone. In a 2019 paper, Tisdale reported such transplants work in about 50% of patients treated.
The gene therapy using a viral vector could potentially reach thousands more people. Preparation for a new clinical trial with 41 patients is now underway.
“This is a phenomenal advance in this terrible disease,” said Neal Young, chief of the Hematology Branch at NIH’s National Heart, Lung, and Blood Institute. “It’s just so gratifying and so important that it’s really being seriously addressed with money, and people like Griff and John.”
That was not always the case. Although the cause of the disease was identified more than 50 years ago, work on treatments was slow to come, Collins said.
Rodgers began the important work of researching therapies for sickle cell disease in the 1990s and played a leading role in the development of hydroxyurea, a drug that reduces the painful crises people with sickle cell disease experience, enabling them to live more normal lives. It has been so successful, the Food and Drug Administration in December of 2017 extended approval to children aged 2 years and older.
Through his contributions, and as a champion for the treatment of sickle cell disease, Rodgers “has attracted and encouraged a host of other scientists to come in and, together, they’re pioneering the effort,” said Peter Agre, Bloomberg distinguished professor at Johns Hopkins School of Public Health, who has worked with Rodgers for 40 years.
“If this kind of work were occurring in another country, Griff’s picture would be on postage stamps,” he said. “He’d be a national hero, no question.”
Rodgers and Tisdale, together, subsequently developed a method of curing sickle cell disease through a blood stem cell transplant, which is effective in 90% of patients but not broadly applicable, because only 10% of people with sickle cell disease have a donor match.
That work then led to the half-match stem cell transplants, gene therapy and the seeds of many more pursuits for curing sickle cell disease. In the meantime, many people with sickle cell disease are living pain-free lives, thanks to the therapies discovered so far.
“Because of the work of Rodgers and Tisdale, research on sickle cell disease is no longer neglected,” Collins said. “It’s some of the most exciting and groundbreaking science there is.”