INTRODUCTION

It has been four decades since the concept of gene therapy for human disease began to be considered and discussed in earnest. With the advent of recombinant DNA technology in the 1970s and the concurrent discovery that viruses could carry novel genetic information into target cells, gene therapy was seen as having significant future potential. A major step in the development of gene therapy for hematopoietic disorders occurred in 1985 when the laboratories of Bernstein and Anderson simultaneously showed that the genome of mouse hematopoietic stem cells (HSCs) could be permanently modified using a genetically engineered retrovirus capable of integrating into host cell DNA. These results suggested that a patient's own HSCs could be harvested, genetically modified ex vivo, and then returned, perhaps following administration of radiation or chemotherapy to eradicate the diseased HSCs. From that time, it took almost a decade before functional correction of human disease model was demonstrated using retroviral-mediated, HSC-targeted gene transfer. The first such description was that of Heard and colleagues when they demonstrated the successful treatment of a murine model of the lysosomal disorder, mucopolysaccharidosis type VII. Subsequently, murine models of two immunodeficiencies – chronic granulomatous disease and a form of severe combined immunodeficiency due to JAK3 deficiency – were also successfully treated using gene therapy. These successes seemed to fulfill the stated goals of the Orkin and Motulsky NIH panel, which called for more basic science research into gene therapy and the use of murine disease models to demonstrate efficacy prior to clinical trials.