Is the First Gene Therapy for Hemoglobinopathies on the Horizon?

Sickle cell disease and beta thalassemia are the most common monogenetic diseases worldwide, with sickle cell disease alone afflicting approximately 100,000 Americans.1 These diseases and other hemoglobinopathies are caused by mutations that affect the expression or function of hemoglobin β-chain, encoded by the HBB gene.

Until recently, bone marrow transplants were the only curative treatment for sickle cell disease and beta thalassemia. While a very valid approach and the bone marrow transplant process has improved over the years, most patients do not have a suitable donor match available to them. Even when an appropriate donor is available, marrow graft rejection risks are high.

Gene therapies are in the early days of commercialization, and, as of today, the FDA has approved only three. However, a significant factor that makes gene therapy so promising for sickle cell disease and beta thalassemia is that there is only one gene at fault versus the complex assortment of genes responsible for most disease states.

The strategies to correct the mutated HBB gene fall into two camps:

  • HBB gene insertion/correction: Directly correct the mutated HBB gene using gene editing or deliver a wild-type copy of the HBB gene to patient cells. These genetically corrected cells can repopulate the bone marrow and produce healthy red blood cells for the remainder of the patient’s life.
  • Silencing BCL11A repression: Genetically disrupt the BCL11A gene in the patient’s hematopoietic stem cells to boost production of fetal hemoglobin—a form of hemoglobin produced by babies until about six months of age. BCL11A is known to repress the expression of fetal hemoglobin. Thus, BCL11A gene disruption turns the production of fetal hemoglobin “back on.” This strategy is particularly promising as it could be used for treating all -globin disorders, irrespective of the underlying genetic mutation in HBB.

There is exciting work being done by a number of research teams, and four efforts appear particularly promising.

  1. Led by Dr. David A. Williams, president of Dana-Farber Cancer Institute and Boston Children’s Hospital, a phase 1 trial is currently underway that utilizes a lentivirus vector to knock down BCL11A—but only in precursors of red blood cells. By knocking down BCL11A to increase the production of fetal hemoglobin rather than using a gene correction strategy, the team is predicting it can develop a more effective approach to reduce or even eliminate the sickling of red blood cells.2
  2. Vertex Pharmaceuticals and CRISPR Therapeutics announced the dosing of the first patient with CTX001 — autologous CD34+ human hematopoietic stem and progenitor cells modified ex vivo with CRISPR-Cas9 at the erythroid lineage-specific enhancer of BCL11A — in a phase 1/2 clinical study of patients with transfusion-dependent beta thalassemia, marking the first company-sponsored use of a CRISPR/Cas9 therapy in a clinical trial. In parallel, the companies are conducting a phase 1/2 trial to evaluate the safety and efficacy of CTX001 in subjects with severe sickle cell disease.3
  3. LentiGlobin BB305, developed by bluebirdbio, is a gene therapy composed of autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene. Several Phase 3 global clinical trials are underway for the treatment of transfusion-dependent beta thalassemia. The correcting of the human beta-A-T87Q globin gene is showing promising signs of facilitating the patient’s ability to make healthy red blood cells.4
  4. Bioverativ, a Sanofi company, and Sangamo Therapeutics collaborated and ultimately secured an investigational new drug (IND) for BIVV003, a gene therapy for the treatment of both sickle cell disease and beta thalassemia.
    BIVV003 uses a non-viral, zinc finger nuclease (ZFN) gene-editing approach to disrupt BCL11A, rather than lentivirus vectors or CRISPR, in patient’s red blood cell precursors which they believe will protect patients against the progression of sickle cell disease. Bioverativ is leading clinical trials for the treatment of sickle cell disease which are showing promising results. Sangamo is treating patients with transfusion-dependent beta thalassemia using the same gene-editing approach as that used in BIVV003.5

There is great reason to be optimistic about the realization of successful gene therapies to treat sickle cell disease, beta thalassemia, and other hemoglobulinopathies. However, there is much work to be done. Will lentivirus gene knockout or CRISPR gene editing be the most effective? Or, perhaps non-viral ZFN gene-editing technology will win the day? We have yet to learn whether an HBB gene-correction strategy will be the most effective, or whether editing the BCL11A gene to resume higher volume production of fetal hemoglobin is the way to go.

Regardless of the approach, flexible development platforms that allow teams to formulate their ideas from concept to commercialization using a single platform are needed to move therapies to the clinic as quickly as possible.

One example of the importance of enabling platforms is the BCL11A work by Sangamo. Using MaxCyte’s ExPERT platform for cell engineering, researchers were able to rapidly develop a method for non-viral, highly efficient, ZFN-mediated gene disruption. Critical to its accelerated path to the clinic was the scalability and regulatory compliance of the platform which alleviated the need to redesign and/or validate new methods for translational research.6, 7

Read full articles from Sangamo and related SCD research:

  • Long-term engraftment and fetal globin induction upon BCL11A gene editing in bone-marrow-derived CD34+ hematopoietic stem and progenitor cells. (link)
  • Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with beta thalassemia major. (link)
  • GMP-compliant Non-viral CRISPR-mediated Process Correcting the Sickle Cell Disease Mutation in SCD Patient CD34+ Cells Achieves 60% Wild Type Adult Hemoglobin Expression in Differentiated Erythrocytes. (link to MX poster)


  1. Sickle Cell Disease Foundation
  2. “Reviving fetal hemoglobin in sickle cell disease: First patient is symptom-free,” Nancy Fliesler, Boston Children’s Hospital blog, December 3, 2018
  3. “Vertex, CRISPR Therapeutics infuse first patient in CRISPR/Cas9-based gene therapy study,” Alaric Dearment, MedCityNews, February 25, 2019
  4. “LentiGlobin Shows Positive Effects in Severe Sickle Cell Disease Patients, Phase 1/2 Data Reports,” Alejandra Viviescas, PhD, December 18, 2108
  5. “Bioverativ And Sangamo Announce FDA Acceptance of IND Application for Gene-Edited Cell Therapy BIVV003,” Reuters, May 18, 2018
  6. Long-term engraftment and fetal globin induction upon BCL11A gene editing in bone-marrow-derived CD34+ hematopoietic stem and progenitor cells. (2017) Mol. Ther. Methods Clin. Dev., 11(4): 137-148.
  7. Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with beta thalassemia major. (2018) Mol. Ther. Methods Clin. Dev., 10: 313-326.