The potential of gene therapy approaches for the treatment of hemoglobinopathies: achievements and challenges

Abstract

Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are a heterogeneous group of commonly inherited disorders affecting the function or levels of hemoglobin. Disease phenotype can be severe with substantial morbidity and mortality. Bone marrow transplantation is curative, but limited to those patients with an appropriately matched donor. Genetic therapy, which utilizes a patient's own cells, is thus an attractive therapeutic option. Numerous therapies are currently in clinical trials or in development, including therapies utilizing gene replacement therapy using lentiviruses and the latest gene editing techniques. In addition, methods are being developed that may be able to expand gene therapies to those with poor access to medical care, potentially significantly decreasing the global burden of disease.

Keywords: gene editing; gene therapy; hemoglobin; hemoglobinopathy; sickle cell anemia; thalassemia.

Figure 1.

Typical process of gene therapy for hematopoietic disorders. Hematopoietic stem and progenitor cells (HSPCs), induced pluripotent stem cells (iPSCs). HSPCs can be modified directly, as is the case for currently used therapies. Alternatively, somatic cells, e.g. fibroblasts, can be first reprogrammed into iPSCs before being modified. A correctly modified iPSC clone is then selected and expanded before being differentiated into HSPCs. In either case, the genetically modified HSPCs are then transplanted back into the patient. When HSPCs are modified directly, modification may not occur in every cell.

Figure 2.

Three most common gene modification strategies using designer nucleases (ZFN, TALEN, and CRISPR/Cas). The given nuclease system identifies a specified region of the genome through base pair recognition (orange hash marks) and creates a DSB (scissor). In the absence of a repair donor, NHEJ DNA repair creates an ‘indel’ (red DNA region) resulting in a gene knockout. If a repair donor is supplied, HR may occur, resulting in incorporation of a designed modification (e.g. insertion, deletion, substitution). Cas, CRISPR associated protein, CRISPR, clustered regularly interspaced short palindromic repeats; DSB, double strand break; gRNA, guide-RNA; HR, homologous recombination; NHEJ, nonhomologous end-joining; TALEN, transcription activator-like effector nuclease; ZFN, zinc-finger nuclease.