Preclinical evaluation of gene transfer products: safety and immunological aspects

As any new drug in development, gene transfer products have to be tested for their potential toxicity in preclinical studies. Strategies for preclinical safety evaluation of gene transfer compounds are similar to those undertaken for biotechnology-derived pharmaceuticals with the added complexity of having to test additional components, such as the vector and genetic material. Some recommendations have been issued by regulatory agencies to provide assistance in the toxicological assessment of gene transfer products before administration to humans. However, the design of such studies is complicated and has to be approached case-by-case. Crucial aspects for safety evaluation are: (1) the choice of animal models with respect to the pharmacological activity of the gene transfer product, the susceptibility to infection in the case of viral vectors, and to the immunogenicity of all entities; (2) biodistribution of the vector after administration, avoiding germinal transmission. Immunological and immunotoxicity endpoints should also be assessed. This paper reviews some of the properties of gene transfer vectors with emphasis on their potential effects on the immune system, and also highlights some of the problems likely to be encountered during the preclinical safety evaluation.