Introduction to a review series on gene therapy and gene editing for sickle cell disease and hemophilia

Advances in stem cell biology and gene engineering have fueled the development of gene therapies for hematologic diseases such as sickle cell disease (SCD) and hemophilia. Bone marrow transplantation (BMT) spurred by advances in haploidentical BMT approaches have gained interest in curative BMT approaches for SCD and hemoglobinopathies such as thalassemia. However, BMT for SCD is limited by the availability of HLA-matched donors and the use of alternative donors is more frequently complicated by immune rejection and graft-versus-host disease. Therefore, gene therapy is an attractive alternative treatment modality for SCD, especially because it results from a monogenic point mutation. Moreover, gene therapy also offers a potential curative approach for patients with hemophilia by establishing continuous endogenous expression of factors VIII or IX following gene transfer. Hemophilia A and B are well suited for gene therapy because relatively minor increases in blood factor levels (≥5% of normal) can result in major clinical improvements in severely affected patients.

Hence, in this review series, experts will evaluate a sample of the current progress of gene therapy for hemophilia and sickle cell disease with an emphasis on the successes and the current hurdles and how to solve them:

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  Frank W. G. Leebeek and Wolfgang Miesbach, “Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues”

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  Allistair A. Abraham and John F. Tisdale, “Gene therapy for sickle cell disease: moving from the bench to the bedside”

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  Richard J. Jones and Michael R. DeBaun, “Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither”

In the first paper, Leebeek and Miesbach discuss the progress made with gene therapy for hemophilia A and B from the first adenovirus-associated virus (AAV)-based liver-directed gene therapy studies for hemophilia B a decade ago to the more recently reported early-phase trials including the preliminary results of phase 2b/3 trials for both hemophilia A and B. In this review, the authors also outline the side effects and drawbacks associated with gene therapy for these diseases including the AAV-specific immunologic response with resultant liver function abnormalities and liver toxicities, acknowledging that such issues must be resolved before gene therapy can be broadly available for the hemophilia patient population.

The second paper by Abraham and Tisdale focuses on the curative potential of gene therapy for SCD. This disease has long been an attractive application for a gene therapy approach given that the SCD phenotype is the result of a single point mutation. The authors discuss the advances in genomic sequencing and gene editing that have made gene therapy for SCD a reality. Unlike gene therapy for hemophilia, which typically use a direct injection (ie, liver-directed) of a viral (AAV-based) vector, the approach for SCD first requires gene modification ex vivo of the patient’s hematopoietic stem cells (HSCs). Therefore, major complexities including the need for HSC mobilization and collection and the administration of a conditioning chemotherapy regimen before gene therapy will need to be overcome to move this gene therapy approach to standard-of-care treatment of SCD.

To that end, finally, and importantly, Jones and DeBaun present a perspective on the development of leukemia after SCD gene therapies, which is one of the most recent and major challenges the SCD gene therapy field has faced. Specifically, the SCD gene therapy trial HGB-206 sponsored by bluebird bio was suspended after the development of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) in 2 patients with SCD enrolled in the study. Potential attributions for these events include the use of busulfan in the chemotherapy conditioning, insertional mutagenesis, both, or neither. The authors present the data and their working hypothesis to explain this development of AML/MDS after gene therapy in SCD.

The gene therapy field has clearly witnessed appreciable growth in recent years with numerous successful achievements. However, multiple challenges remain that still need to be overcome before gene therapy becomes widely available for all patients afflicted with these blood disorders. We hope that this series by leaders in the field will prove of interest to our broad readership from laboratory researchers to clinical hematologists alike.