New approach to gene therapy helps smooth road for people with sickle cell disease

Gene therapy has been transformative for individuals with sickle cell disease, a genetic condition caused by a mutation in the adult form of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. As a result, red blood cells stiffen and change shape, leading to pain, anemia, blood clots, and other health problems. However, the current approach to gene therapy that uses a patient’s own blood stem cells requires multiple hospital visits to collect enough cells — a lengthy process that some patients hesitate to undergo.

Now, researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have helped smooth the road to gene therapy with an approach that can collect and manufacture enough stem cells much more efficiently, almost always in a single hospital admission.

Improving the process

FDA-approved commercial gene therapy technologies for treating hemoglobin disorders can require multiple sessions to successfully collect enough blood stem cells. Additionally, prolonged manufacturing can delay infusing the modified cells back into the individual. In the approach led by David A. Williams, MD, chief of Boston Children’s Division of Hematology/Oncology, Erica Esrick, MD, and John Manis, MD, 10 of 11 people with sickle cell disease had enough blood stem cells collected in one session at Boston Children’s. Then, the stem cells from each participant in the pilot trial were genetically modified and cryopreserved at the Connell and O’Reilly Families Cell Manipulation Core Facility at Dana-Farber Cancer Institute. After safety testing at the Boston Children’s Therapeutic Innovation Laboratory, the genetically altered stem cells were infused back into patients with an average turnaround time of seven weeks compared to industry times that can take as long as six months or even longer. Patients did not experience unexpected safety events related to the collection, manufacturing, or transplantation of their stem cells. The researchers’ report includes follow-up of patients for up to seven years after undergoing gene therapy.

The approach used is based on fundamental research also done at Boston Children’s by Stuart Orkin, MD, and his colleagues, who co-discovered how fetal hemoglobin shuts off when red blood cells develop during the first year of life. Williams’ team developed an efficient process using a virus to reactivate the fetal hemoglobin gene in the patient’s own stem cells, while simultaneously shutting off the sickle cell gene. The approach was subsequently expanded into a national, multicenter study that has now completed enrollment.

“We have figured out how to overcome some of the barriers to transforming the lives of individuals with sickle cell disease and are excited with these results,” says Williams.

Expanding access to a life-changing therapy

Based on the safety findings of the pilot trial, the FDA and NIH approved and funded an ongoing multisite trial for an additional 25 participants. Most recently, the FDA approved extending the therapy beyond these first two studies through the Expanded Access Program. This allows more patients to be treated before a formal application for drug approval. Additionally, the team licensed the technology to Caring Cross, a nonprofit dedicated to expanding access to cell and gene therapies globally, which is now opening trials in Brazil and India, home to large populations of people with sickle cell disease who could greatly benefit from the therapy.

“As the first human trial for this approach, these results from this initial study helped establish the most effective way to apply the process of collecting and engineering enough of the patient’s own cells to guide the subsequent national study, which has now also completed full enrollment with a total of 36 individuals treated to date,” says Williams.

Learn more about the sickle cell disease gene therapy clinical trial.