Toward gene therapy for disorders of globin synthesis

Inherited disorders of hemoglobin remain desirable targets for genetically based therapies. That stem cell replacement reverses the phenotype of both thalassemia and sickle cell anemia has been well established through allogeneic bone marrow transplantation studies, yet significant toxicities and finite donor availability limit this approach to a minority of affected individuals. Genetically based strategies that have as their goal addition of a normal copy of the human beta-globin gene along with key regulatory sequences to autologous hematopoietic stem cells represent a viable alternative to allogeneic transplantation, but this approach has been impeded by formidable obstacles over the last decade. Large animal models have become the standard for the development of clinically relevant gene addition strategies, and significant progress in the techniques used to deliver potentially therapeutic genes has been achieved. The clinical application of such strategies may be close at hand, at least for disorders in which modest level, constitutive expression is sufficient to correct the phenotype. For the thalassemias and hemoglobinopathies, complex, regulated, lineage specific expression of the beta-globin gene at relatively high levels will be required. The discovery of the beta-globin locus control region renewed interest in the thalassemias and sickle cell anemia as targets for gene transfer, but difficulties in attaining high-titer vectors along with a tendency toward rearrangement when segments of the locus control region (LCR) were incorporated into retroviral vectors stalled further progress. Recent advances in vector construction have circumvented this problem and others limiting both gene transfer efficiency and regulation of transgene expression, offering new hope for clinical application.