Updates in Stem Cell Transplant and Gene Therapy for Sickle Cell Disease

by Dr. Nicole De Simone

The American Society of Hematology (ASH) recently published guidelines for stem cell transplantation in patients with sickle cell disease (SCD).1 Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for SCD, but risks of transplant must be balanced with the potential patient benefits. The ASH guidelines address the use of HSCT in SCD patients with neurologic injury, frequent pain, or acute chest syndrome (ACS). Guidelines also address type of transplantation, optimal donor, and recipient age. The ASH guideline panel suggests matched related HSCT rather than standard of care (hydroxyurea/transfusion) in SCD patients who 1) have experienced an overt stroke or have an abnormal transcranial Doppler ultrasound, 2) have frequent pain, or 3) have recurrent episodes of ACS. The ASH guideline panel suggests for an allogeneic transplant to occur at an earlier age rather than an older age. The panel suggests the use of a high-quality HLA-identical sibling cord blood transplant when available over bone marrow.

SCD is the most prevalent single-gene disease, and has long been a target for gene therapy. Clinical trials for SCD treatment utilizing gene-addition therapy to modify patient CD34+ cells with the addition of a β-globin gene first began in 2006 with the French study protocol LG001 using a lentiviral vector for ex vivo transduction.2 More recently, gene-editing technology has been developed that allows for correction of the point mutation in the β-globin gene or modification of regulatory genes to induce fetal hemoglobin (HbF or α2γ2) production, and numerous clinical trials for each of these gene-editing strategies are currently underway.3

The BCL11A gene represses expression of γ-globin, inhibiting production of HbF in adult red blood cells. The goal of BCL11A-targeted gene therapy is the reversal of hemoglobin switching, leading to an increase in HbF (and decrease of HbS). An increase in HbF level provides partial correction of SCD. An HbF fraction of 20 percent has been reported as the threshold level needed to significantly lessen the clinical severity in SCD.4 A recent publication in the New England Journal of Medicine describes results for six patients enrolled in the BCL11A gene editing clinical trial NCT03282656.5 Patients were enrolled in the single-center pilot study involving infusion of autologous stem cells after transduction with the BCH-BB694 lentiviral vector encoding a short hairpin RNA embedded in an endogenous microRNA (shmiRNA) targeting erythroid lineage-specific knockdown of BCL11A. Patients were eligible for this study if they had clinically severe SCD and no HLA-matched sibling available to serve as a stem cell transplant donor.

Study results describe the clinical and laboratory response and safety for six SCD patients followed for seven to 29 months after autologous gene therapy infusion. All patients engrafted after infusion with median times to engraftment of 22 days for neutrophils and 33 days for platelets. An increased HbF fraction was maintained in all patients. One patient continued regular transfusions but at a lower frequency than prior to gene therapy. For the five untransfused patients, the median HbF fraction at the most recent study visit was 30.4 percent (range, 21.6 to 40.0). Hemolysis continued in all patients but was reduced from baseline levels as measured by absolute reticulocyte count and lactate dehydrogenase levels. No patient had a vaso-occlusive crisis, ACS, or stroke after gene therapy infusion. One patient with left hip avascular necrosis prior to gene therapy, developed symptoms of right hip avascular necrosis nine months after gene therapy. One patient had who had required frequent hospitalizations for priapism prior to gene therapy required two hospital admissions for recurrent priapism approximately four months after infusion. This patient did not require any emergency department visits or hospitalizations for priapism since month eight after gene therapy. The overall findings of this study demonstrate a favorable safety profile of this autologous gene therapy. Further, the HbF levels maintained in the study patients after BCL11A-targeted gene therapy are associated with meaningful reduction in the clinical severity of disease.

References:

  1. Kanter J, Liem R, Bernaudin F, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5(18): 3668-3689.

  2. Negre O, Eggimann A, Beuzard Y, et al. Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the βA(T87Q)-Globin Gene. Hum Gene Ther. 2016;27(2):148-165.

  3. Germino-Watnick P, Hinds M, Le A, et al. Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease. Cells. 2022;11:1843.

  4. Powars DR, Weiss JN, Chan LS, et al. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood. 1984;63(4):921-926.

  5. Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N Engl J Med. 2021;384(3):205-215.