Herpes simplex viral vectors: late bloomers with big potential.

My interest in gene therapy began in the early 1980s as a fresh associate professor at the University of Michigan. The University of Michigan had just recruited a new wave of young scientists who went on to become important leaders in the field of molecular medicine, including Francis Collins (current NIH director), Gary Nabel (chief scientific officer at Sanofi), Betsy Nabel (president of Brigham and Women's Hospital), Graig Thompson (CEO of Sloan Kettering Memorial), Jeffrey Leiden (CEO and president of Vertex Pharmaceuticals), and James Wilson (director of the Penn Gene Therapy Program). Most were appointed in medicine, where William Kelley (former CEO of the Penn Health System and dean of the School of Medicine) was chair. I had the good fortune to work with and be influenced by these talented scientists and particularly by Bill Kelley, who was a visionary leader and a huge proponent of gene therapy, including the development of herpes simplex viral (HSV) vectors for treatment of Lesch Nyhan disease (Palella et al., 1989). I was also blessed by my association with Myron (Mike) Levine in the Department of Human Genetics. Mike took me under his wing and taught me how to use genetics to study virus biology, whereupon his insights influenced me for the rest of my career. The potential for genetic intervention in the treatment of human disease began essentially with the advent of genetic mapping of disease genes and determination of their resulting pathologies. It appeared that gene therapy offered unlimited potential for “curing” at least recessive inborn errors of metabolism by gene “replacement” therapy. The most important question was how to get the therapeutic gene into the correct tissue with appropriate level and duration of expression. Because viruses could efficiently enter and replicate in cells of the body reflecting their unique biology and host cell preferences, it appeared that recombinant viruses could be engineered as effective gene delivery vehicles by replacing pathogenic genes with therapeutic sequences. I became intrigued with the concept of viruses as universal gene delivery tools. On the basis of the fact that herpes viruses persisted in humans in a latent state for life with preference for specific cell types, it seemed feasible to exploit this group of human viruses for gene therapy. Since some therapeutic gene cassettes were likely to be large, especially in combination with complex regulatory elements, large payloads would require large vectors. I became convinced that HSV could fill this niche, particularly for gene delivery to the nervous system, the natural site of HSV latency. However, when we began these studies, there was relatively little known about the molecular biology of HSV replication and pathogenesis, requiring us to peel back many layers of vector-engineering complexities to create a useful gene delivery platform. This quest has taken 30 years of work, beginning at the University of Michigan and continuing at the University of Pittsburgh, and only recently do I think we have succeeded in creating broadly useful vector designs. Our headway in vector engineering also addressed other pressing vector problems that included the need for low effective dosing with minimal inflammatory responses, targeted infection and long-term gene expression in specific cell types, and the ability to rapidly produce and manufacture vectors for clinical applications.