Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy

The development of viral vectors has been particularly critical for genetic therapies of hematological diseases. Before the development of retrovirus vectors (RVVs), gene transfer into mammalian cells was accomplished by transduction of DNA plasmids by chemical means and later by electroporation. The main limitation of these methods is the inefficiency of transfer of intact sequences, and particularly with electroporation significant cell death of the manipulated cells. The earliest successful human gene therapy trials utilized gamma-RVVs and many of the techniques developed in the 1980s. A breakthrough for the field was the exploitation and development of HIV for transfer vectors, termed lentivirus vectors. In this review, we highlight uses of retro-and lentivirus vectors in monogenic diseases in which hematopoietic stem cells are used in the autologous setting to treat immunodeficiencies, hemoglobinopathies and metabolic diseases. The three authors' perspective represent experiences in the field over four decades that encompasses both basic translational research and development and oversight of early and ongoing gene therapy trials utilizing viral vectors.