Evolution of a gene therapy clinical trial. From bench to bedside and back.

Developing and conducting gene therapy clinical trials poses unique challenges which must be addressed to satisfy regulatory requirements and, most importantly, to protect human subjects. Experimental products used for gene transfer studies, such as viral vectors, are often complex and cannot be sterilized or completely characterized to the extent of a typical pharmaceutical. Thus, quality and characterization must be built into the production process. Extensive preclinical studies must be performed to determine the feasibility of the approach, the safety of the product, and the appropriate dose range to evaluate in humans. Once a clinical trial is initiated, subjects must be followed carefully for short- and long-term toxicity especially since preclinical studies may not adequately predict the toxicity profile of these novel, complicated products. Results of early phase studies in gene therapy have often sent the investigators back to the laboratory to improve the delivery vector or identify a more potent or less toxic gene. This circular developmental process is expected for the early stages of a new technology such as gene therapy. Although these hurdles appear extensive, they can be overcome, as evidenced by the initiation of more than 500 clinical gene therapy trials in the United States to date, and are imperative for the maintenance of high-quality studies and public trust. This article describes the step-by-step process for developing a gene therapy trial incorporating specific examples relevant to neuro-oncology.