Reviving fetal hemoglobin in sickle cell disease: First patient is symptom-free

Erick Esrick, MD, of Boston Children's Hospital, with patient

Manny Johnson of Boston, 21, previously required monthly blood transfusions to keep his severe sickle cell disease under control. After receiving a new gene therapy treatment, he’s been symptom-free for six months.

Researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center reported Manny’s case Saturday at the American Society of Hematology meeting in San Diego. Manny is their first patient, and an ongoing clinical trial will treat additional patients between ages 3 and 40.

The gene therapy treatment, based on 70 years of research, silences a gene called BCL11A. This has enabled Manny’s cells to produce the fetal form of hemoglobin, which his sickle-cell mutation doesn’t affect. The treatment also suppresses his adult, sickling hemoglobin. Manny hopes the same treatment could help his younger brother, now 7, who also has sickle cell disease and is cared for at Boston Children’s.

Restoring fetal hemoglobin

Most people stop making fetal hemoglobin soon after birth. But it’s been known since the 1970s that certain people with the sickle cell mutation continue to produce fetal hemoglobin and have a milder form of the disease. In 2008, Vijay Sankaran, MD, PhD and Stuart Orkin, MD of Dana-Farber/Boston Children’s zeroed in on a gene called BCL11A, which switches off fetal hemoglobin. In a 2011 study, Orkin’s team suppressed BCL11A in a mouse model, and successfully reversed sickle cell disease.

Led by David A. Williams, MD, president of Dana-Farber/Boston Children’s, researchers went on to engineer an optimized gene therapy vector that is more precise in its action.

“Our approach is unique in that it uses the physiology of the hemoglobin switch to simultaneously increase fetal hemoglobin and directly reduce sickling hemoglobin,” says Williams, who is also chief scientific officer at Boston Children’s Hospital and lead investigator on the clinical trial. “Other trials are adding genes that encode fetal hemoglobin or corrected, non-sickling adult hemoglobin, without directly decreasing expression of the sickle hemoglobin gene. We predict this strategy is a much more effective way to reduce or even eliminate the sickling of cells.”

Six months out from treatment, Manny’s blood has significantly increased levels of fetal hemoglobin and appears to be free of sickled cells.

Treating Manny

Manny was hospitalized for his treatment. The team collected his blood, isolated the blood stem cells and exposed them to the gene therapy vector. The vector, a lentivirus, bore instructions to knock down BCL11A, but only in precursors of red blood cells. Manny then received chemotherapy to make way for the gene-modified cells, which were returned to him through an intravenous infusion.

“The day Manny received his cells back was a pretty emotional day for the whole team,” says Erica Esrick, MD, co-principal investigator on the clinical trial and a pediatric hematologist-oncologist at Dana-Farber/Boston Children’s.

Until now, the only curative treatment for sickle cell disease has been a bone marrow treatment. “While that works, and it’s getting better and better, there are a number of patients who don’t have a good match,” says Williams. “If this new technology we’ve developed works, then the person can be their own donor.”

The investigator-initiated clinical trial is funded by the National Institutes of Health. Others involved in the trial include co-principal investigator Alessandra Biffi, MD, as well as Matthew Heeney, MDLeslie Lehmann, MD, Wendy London, PhD, and John Manis, MD, at Dana-Farber/Boston Children’s, and Maureen Achebe, MD, MPH at Brigham and Women’s Hospital. The vector technology developed in Williams’s laboratory has been licensed to bluebird bio in Cambridge, Mass.

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