The U.S. Food and Drug Administration (FDA) approvals of the first cell-based ex vivo gene therapies for beta thalassemia and sickle cell disease (SCD) mark a significant scientific achievement. Two physician-
scientists, Stuart H. Orkin, MD, and John F. Tisdale, MD, made key research contributions that helped make these life-changing innovations possible.
Stuart H. Orkin, MD John F. Tisdale, MD
Dr. Orkin is the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School in Boston and a Howard Hughes Medical Institute investigator. Among his other contributions, Dr. Orkin identified the BCL11A gene as a therapeutic target to turn on the expression of fetal hemoglobin after infancy, which could be then used in clinical gene editing trials in SCD and beta thalassemia.
Dr. Tisdale is the chief of the Clinical and Molecular Therapeutics Branch of the National Heart, Lung, and Blood Institute at the National Institutes of Health. Dr. Tisdale’s efforts in hematopoietic cell transplantation led to work that contributed to protocols for safe and effective ex vivo gene transfer in gene therapy, as well as for reduced conditioning pretransplant.
As part of the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, Drs. Orkin and Tisdale will present this year’s Ernest Beutler Lecture, named for the late physician-scientist and past president of ASH. The two-part lectureship and associated prize recognize major advances on a single topic, one with emphasis on basic science and the other more rooted in clinical science or translational research.
Both speakers will discuss their involvement in the scientific discoveries that helped lead to current gene therapies for SCD, and they will also address current research questions and future innovations. Although the lecture will focus on developments related to SCD, both Drs. Tisdale and Orkin noted that the lecture will be relevant to those interested in genetic interventions for diseases more broadly. The development of SCD gene therapies has provided first-in-human applications of techniques and technologies with much wider applicability.
“And thinking about how to make these therapies even better, more widely accessible, could have huge implications for other genetic conditions,” Dr. Orkin said.
Dr. Tisdale noted that the dream of finding a molecular cure for SCD dates to Linus Pauling’s first description of its molecular basis. “That was 1949, so it’s about time, but it’s just amazing to have something like this for SCD,” he said.
Dr. Orkin said the field has known since the 1940s that fetal hemoglobin protects against severe clinical consequences in patients with SCD; the idea of potentially regulating the switch from fetal to adult hemoglobin has been a vision in the field for decades.
Dr. Orkin and colleagues used new gene cloning technologies to determine the diverse mutations in the adult beta globin gene in beta thalassemia. Afterward, he and trainees identified the GATA1 transcription factor, which controls all genes in developing red cells. However, this work didn’t solve the problem of the fetal switch because GATA1 is present in both fetal and adult stages.
The discovery of BCL11A as a candidate regulator of fetal hemoglobin expression arose from genome-wide association studies in late 2007 and 2008. Follow-up studies showed that BCL11A acts to silence fetal hemoglobin production in adult stage cells. Although Dr. Orkin and others in the field initially worried that many factors might control the fetal-to-adult switch, the actual mechanism controlling the fetal-adult switching system turned out to be surprisingly simple (with BCL11A as a repressor of fetal [g-]globin gene expression).
Turning the discovery of BCL11A into a potential therapy, however, required further technical developments. Eventually, Dr. Orkin and colleagues used CRISPR gene editing to locate a single position within a regulatory element in the BCL11A gene that is critical for its expression, and hence fetal hemoglobin silencing. Cutting this region with CRISPR alleviates repression and allows for reactivation of fetal hemoglobin to a therapeutic level. This approach was brought to patients in the exagamglogene autotemcel (exa-cel) trials for both SCD and beta thalassemia, which culminated in regulatory approvals.
However, this would not have been possible were it not for complementary work by Dr. Tisdale and colleagues. Their work was also critical for successful implementation of the lovotibeglogene autotemcel (lovo-cel) SCD gene therapy, based on lentiviral introduction of a modified beta globin gene to produce anti-sickling hemoglobin.
Dr. Tisdale will discuss some of his work on developing safe and effective protocols for allogeneic hematopoietic cell transplant, such as with chemotherapy-free (reduced-intensity) conditioning. Concurrently, over many years, he and his team used animal models to develop and refine strategies for autologous transplant of genetically modified cells.
Dr. Tisdale noted it was initially very difficult to get enough replication of the genetically modified cells compared with remaining (non-genetically modified) cells after engraftment. They had to learn how to carefully treat the modified hematopoietic cells while they were outside of the body so they would still successfully engraft once readministered to the patient.
They and others in the gene therapy field also encountered challenges from undesired viral vector integration leading to leukemias. They eventually moved to a lentiviral delivery approach, ultimately optimizing the transduction and conditioning protocols to achieve a high enough percentage of modified hematopoietic cells engrafted for therapeutic efficacy. Eventually, this work contributed to approval of the lovo-cel gene therapy. Dr. Tisdale’s group also contributed to work on exa-cel, which he will discuss as well.
Dr. Orkin pointed out that these accomplishments in gene therapy, although impressive, are not well suited to reducing the overall burden of disease of either SCD or beta thalassemia, in the U.S. or abroad. Other innovations will be needed to achieve this goal.
For example, Dr. Tisdale hopes to pursue in vivo gene therapy approaches in the next phase of his career. Theoretically, an in vivo method might allow for much less expensive treatments and less intense monitoring requirements post-transplant. Dr. Orkin also plans to discuss work on developing oral medications that would boost fetal hemoglobin to levels similar to those elicited by genetic methods.
“We’re at a pivotal turning point in the field,” Dr. Orkin noted. “We’re not going to solve this problem by editing genes, at least not the way we’ve been doing it. I want to make sure everyone appreciates that the job isn’t yet done.”
Ernest Beutler Lecture and Prize
Monday, December 9, 1:30 p.m. - 2:30 p.m., San Diego Convention Center, Hall B
