$100K Brinster Prize awarded to researcher for SCD gene therapy

Harvard professor hopes lab's work will inspire others in science

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration of a person delving into a gene therapy, shown as a psychologist taking notes on a DNA strand laying on a couch.

A scientist whose discoveries paved the way for the development of an investigational gene therapy for sickle cell disease (SCD) and other blood disorders has been awarded the third Elaine Redding Brinster Prize in Science or Medicine.

Stuart Orkin, MD, received the award — given annually to a researcher who has made an impactful discovery in biomedicine — from the Institute for Regenerative Medicine at the University of Pennsylvania (Penn). The prize comes with $100,000, a commemorative medal, and an invitation to present a ceremonial lecture at Penn.

Orkin’s “discovery of unexpected details in how the fetal hemoglobin gene is regulated suggested insights for a therapy, for which he availed of the latest gene editing technologies to develop a specific clinical application for sickle cell disease,” Ken Zaret, PhD, the director of the Institute for Regenerative Medicine, said in a university press release.

“I am very honored, and humbled, by recognition with the Brinster Prize,” said Orkin, who is the David G. Nathan distinguished professor of pediatrics at Harvard Medical School and an investigator at the Howard Hughes Medical Institute.

“I hope that work of my laboratory will inspire others to pursue a career of fundamental discovery for the benefit of patients,” Orkin added.

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There are two versions of hemoglobin, the protein that helps red blood cells carry oxygen. The fetal type, known as HbF, is produced in utero — before a baby is born — and is replaced after birth by an adult version called HbA that has a lower affinity for oxygen.

HbA contains beta-globin subunits, encoded by the HBB gene, whereas HbF contains gamma-globin subunits, encoded by the HBG geneIn SCD, mutations in the HBB gene lead to the production of a faulty version of adult hemoglobin.

Switching back on HbF production is thought to be a promising therapeutic approach for easing the severity of both SCD and beta-thalassemia, a blood disorder characterized by problems in producing beta-globin subunits.

Orkin’s team discovered a molecular mechanism that underlies the switch from HbF to HbA. Their work identified a protein called BCL11A that is involved in shutting off HbF production.

The scientists believed that by reducing BCL11A levels, they could boost HbF production, compensating for the faulty or deficient HbA in these disorders.

Proof-of-concept experiments in mice indicated that partially silencing the gene responsible for producing BCL11A did indeed boost HbF production.

These discoveries and others ultimately culminated in the development of an investigational gene therapy called BCH-BB694. It uses gene-editing tools to reduce BCL11A gene’s activity in a patient’s own blood stem cells as a way of increasing HbF.

Dr. Orkin has beautifully illustrated how a career of basic science investigation into the mechanisms for gene regulation can be applied, in one’s own laboratory, to a method for combating devastating human diseases.

An ongoing Phase 1 clinical trial (NCT03282656) is testing the therapy in 10 SCD patients with severe disease. Trial data published last year indicated that the therapy increased HbF production and eased SCD disease manifestations in all but one treated patient.

Based on these promising findings, a Phase 2 trial (NCT05353647), dubbed GRASP, was launched in July 2022. It is evaluating BCH-BB694’s safety and efficacy in up to 25 SCD patients. The study may still be recruiting at sites in the U.S.

“Dr. Orkin has beautifully illustrated how a career of basic science investigation into the mechanisms for gene regulation can be applied, in one’s own laboratory, to a method for combating devastating human diseases,” said Zaret, also a professor at Penn’s Perelman School of Medicine.

“We are thrilled that Dr. Orkin is the third awardee of the Elaine Redding Brinster Prize,” Zaret said.

Orkin will accept the prize in March as part of a symposium at Penn. The researcher has been honored with a number of other awards for his work, including the Canada Gairdner International Award, the Gruber Foundation Prize in Genetics, the King Faisal Prize in Medicine, the Kovaleno Medal of the National Academy of Sciences, and the Harrington Discovery Institute Prize for Innovation in Medicine.