Perspectives Series: Molecular Medicine in Genetically Engineered Animals

“Molecular Medicine in Genetically Engineered Animals” Series Editor, Kenneth R. Chien January 1 Gene modification via “plug and socket” gene targeting................................. Jada Lewis, Baoli Yang, Biological insights through genomics: mouse to man ..................................... Pete Detloff, and Oliver Smithies January 15 Biological insights through genomics: mouse to man ..................................... Edward M. Rubin and Gregory S. Barsh February 1 In vitro differentiation of murine embryonic stem cells: new approaches to old problems .................................................................... Mitchell J. Weiss and Stuart H. Orkin February 15 Genes and physiology: molecular physiology in genetically engineered animals......................................................................................... Kenneth R. Chien March 1 Animal models of human disease for gene therapy........................................ James M. Wilson March 15 Targeted mutagenesis: analysis of phenotype without germline transmission.................................................................................................... Andras Nagy and Janet Rossant April 1 Transgenesis in the rat and larger mammals.................................................. John Mullins and Linda Mullins April 15 Zebrafish: heritable diseases in transparent embryos .................................... Mark Fishman and Wolfgang Driever May 1 Recent advances in conditional gene mutation by site-directed recombination............................................................................. Jamey Marth and Klaus Rajewsky Gene therapy is in its formative stages with the scientific principles requisite for its success only beginning to be defined. The process of discovery and development necessary to make gene therapy a reality differs from that of traditional drug development in several important ways. The basic concept of gene therapy is so fundamental, i.e., modification of gene expression for therapeutic gain, and dependent on an understanding of basic biological principles, that one can expect rapid evolution of the field in directions that will be difficult to predict. Critical advances will emerge from research that focuses on basic biology of the vector systems and target cells. Animal models of human diseases have been emphasized in the early development and evaluation of gene therapy. This has been particularly evident in the evaluation of gene therapy protocols for clinical trials by the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health (NIH). Investigators are advised in the “Points to consider” of the RAC to “Provide results that demonstrate the safety, efficacy, and feasibility of the proposed procedures using animal and/or cell culture model systems, and explain why the models chosen are the most appropriate” (1). It has been five years since the first human gene therapy trial was initiated with greater than 120 others having achieved RAC approval. During this time, tremendous progress has been made in the development of animal models of human diseases through directed germ line manipulation of the mouse. In this short review, I have attempted to assess the impact animal models have had on the early development of the field. This discussion is limited to the use of genetically modified animals in assessing efficacy of gene therapy and defining the basic biological principles relevant to its successful development. I do not address the critical importance of animal models for determination of safety which are traditionally viewed in the context of toxicology.