Bad , and the Ugly Jeffrey

During the last several years, we have witnessed “the best of times and the worst of times” in the embryonic field of gene therapy. Rapid advances in human genomic sciences, the development of novel mouse models of human diseases, and the construction and characterization of new vector systems for in vivo gene transduction have significantly expanded the potential feasibility of human gene therapy. On the other hand, the tragic events surrounding the gene therapy–related death of Jessie Gelsinger and subsequent revelations about additional unreported gene therapy–related complications have seriously damaged both the scientific credibility and public confidence in gene therapy. Given these recent events, this would seem to be an opportune time to pause and carefully reassess where we are and, more importantly, where we should be going in this promising but controversial field. Toward this end, I would like to consider 3 distinct but related questions. First, does the currently available scientific evidence support the feasibility of human gene therapy? If so, what types of preclinical data are necessary to justify human clinical experimentation? Second, what can be learned from our recent experiences about the design of future human gene therapy trials? And, third, what safeguards are necessary to ensure the objectivity of investigators in the field and to thereby inspire the required level of confidence on the part of patients and their families, the scientific community at large, and the general public? The Science: Genes, Vectors, and Devices Most successful gene therapy approaches require the combination of an efficacious therapeutic gene, an appropriate vector for delivering and expressing that gene in the desired cell type in vitro or in vivo, and, in some cases, a device (eg, a catheter, stent, or implantable polymer) to facilitate in vivo gene delivery. The identification of potentially useful therapeutic genes has progressed rapidly during the last decade. Such genes include those involved in inherited single gene disorders such as hemophilia (factors VIII and IX), cystic fibrosis (CFTR), or Duchenne muscular dystrophy (dystrophin) as well as genes that could be used to treat more complex diseases, such as restenosis after balloon angioplasty (eg, the retinoblastoma gene product [Rb] or herpes simplex virus thymidine kinase gene [HSVtk]) or ischemic cardiomyopathies (eg, vascular endothelial growth factor [VEGF] or fibroblast growth factor). This already large list of potential therapeutic genes promises to expand considerably over the next several years with the completion of the human genome project and the identification of additional human diseaserelated genes. An essential first step on the road to human gene therapy, and one that has often been forgotten in the rush to human trials, is a careful assessment of the efficacy and safety of expressing potential transgenes in different tissues in animal models of human disease. In some cases, it is clear from