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Gene Therapy for Hemoglobinopathies

By Haya Harris

Over the last 2 decades, significant advances have been made in gene therapy for hemoglobinopathies. Gene therapy has exploited the ability of retrovirus (RV) vectors, which are equipped with the machinery to reverse transcribe their RNA into complementary DNA (cDNA) and integrate this cDNA into the host cell genome to deliver therapeutic genes into cells. (1)

Hemoglobinopathies are genetic disorders that affect the structure and production of hemoglobin molecules, which consist of polypeptide chains whose chemical structure is genetically controlled. Hemoglobinopathies have the additional challenge of requiring high levels of β-/γ-globin gene expression for therapeutic correction. Identification of critical regulatory elements needed for high expression of the β-globin transgene has made gene therapy for β-hemoglobinopathies (sickle cell disease [SCD] and β-thalassemia) a feasible option. More recently, encouraging results from the first successful gene therapy for a patient with hemoglobin E-β-thalassemia in a French trial has opened up gene therapy as a potential definitive treatment option for patients with β-hemoglobinopathies.

Hemoglobinopathies are inherited genetic conditions that originate from a lack or malfunction of the adult hemoglobin protein. Thalassemia and other diseases associated with β-globin abnormal amino acid sequences — such as sickle cell disease (SCD) and hemoglobin E (HbE) — are some of the most common hemoglobinopathies. Severe anemia combined with complications that arise in the most affected patients raises the necessity for a cure to restore hemoglobin function.

Although clinical trials have been opened worldwide and pre-clinical studies for addressing the accumulating issues identified in previous clinical trials have shown successful outcomes, the high cost of current ex vivo HSC gene therapy is one of the major barriers to the widespread application of gene therapy to β-hemoglobinopathies. The main factor driving the high cost is the large amount of GMP vector production required to adequately transduce HSC. The use of transduction enhancers (2-5) might reduce the number of vectors required to achieve a good HSC transduction efficiency. In addition, novel and more effective LVs that correct the β-thalassemia and SCD phenotype with a low VCN per cell could also decrease the need for large volumes of viral preparations. Recently, one stable producer cell line has been described for a SCID-X1 lentiviral-based gene therapy trial and if available, it should represent another step forward to reduce the cost of these viral preparations. Finally, genome editing-based strategies might be less expensive: manufacturing costs of clinical-grade edited cells are likely lower than those associated with LV-based approaches.

Gene replacement therapy is beginning to show clinical efficacy in those hemoglobinopathies that can be readily corrected with a 3- to 5-g/dl increase in hemoglobin. Improvements in the vector design to increase vector potency can improve the therapeutic efficacy. Newer gene-editing efforts could help circumvent some of these issues, although they are still at early stages and have their own limitations. In the β-laminopathies, gene-corrected HSCs do not have a survival advantage, and therefore, a high degree of chimerism for gene-modified HSCs is necessary. Furthermore, a high level of hemoglobin production per vector copy is also necessary. As such, the HSC dose, the type of chemotherapy conditioning, its intensity, and vector potency are all critical to success. There is certainly room for improvement, but it is clear that HIV-1-based vectors are becoming vehicles of successful therapeutics for hemoglobinopathies.


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