Of Mouse Models and Men
Authors: David A Williams
Journal: Molecular Therapy (2007)

In this issue of Molecular Therapy, Li et al.1Li H Murphy S Giles-Davis W Edmonson S Xiang Z Li Y et al.Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes.Mol. Ther. 2007; 15: 792-800Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar weigh in on the issue of animal studies as preclinical tools for development of human gene therapy trials. Roland Herzog2Herzog RW Immune responses to AAV capsid: are mice not humans after all?.Mol. Ther. 2007; 15: 649-650Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar provides an articulate summary of this and other studies in which mouse models are used to examine the efficacy of adeno-associated viral (AAV) vectors for expressing transgenes to treat hemophilia. Recently, Perel et al.3Perel P Roberts I Sena E Wheble P Briscoe C Sandercock P et al.Comparison of treatment effects between animal experiments and clinical trials: systematic review.BMJ. 2006; 334: 197Crossref PubMed Scopus (574) Google Scholar published a systematic review of the comparison of treatment effects between animal experiments and clinical trials. Also in this month's issue of Molecular Therapy, an article from our laboratory examines the high rate of endogenous lymphoma formation in mice used for safety, so-called ‘bridging studies', for preclinical assessment of retrovirus vectors.4Will E Bailey J Schuesler T Modlich U Balcik B Burzynski B et al.Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trials.Mol. Ther. 2007; 15: 782-791Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The results of all of these studies, not surprisingly, suggest that mice are not men. This is a lesson we previously learned in the world of cancer therapeutics, where therapies that are almost uniformly successful in mice have little efficacy in humans. One of the consequences of both the death of Jesse Gelsinger and the development of leukemia in the severe combined immunodeficiency (SCID) trial in Paris has been increased focus on animal safety and efficacy studies and, particularly, inclusion of these data in the informed-consent process. This is entirely reasonable. However, it is increasingly clear that interpreting such animal studies may be difficult. Even years after the SCID-associated leukemias were reported, the development of leukemia in mouse models of interleukin-2 receptor γ transgene expression by retrovirus vectors remains controversial. In this issue of Molecular therapy, both Li et al. and Herzog point out that mice, apparently unlike humans, are unable to generate an effective cytotoxic response to AAV vector-transduced liver cells. Thus, even in retrospect, both the presence and mechanism of transaminitis and the loss of expression seen in human AAV factor IX hemophilia trials, presumably due to a cytotoxic T-cell response, are difficult to model. In reviewing trials not associated with gene therapy, Perel et al. found significant differences between animal and human studies related, at least in part, to the “failure of animal models to mimic clinical disease adequately.” In our own studies,4Will E Bailey J Schuesler T Modlich U Balcik B Burzynski B et al.Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trials.Mol. Ther. 2007; 15: 782-791Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar we found unexpectedly high rates of endogenous tumor formation in mice, similar to findings only recently reported by others in the literature. The appearance of these tumors requires that preclinical studies be carefully designed to reduce the significant effort required to analyze the origin and mechanism of tumor formation and the interruption in clinical trials necessitated when animal studies show such side effects. This is, of course, an issue not restricted to the academic fields of cell and gene therapy. Consider the number of promising new agents that are abandoned both early and late in development by pharmaceutical and biotechnology companies because of apparent animal toxicities. Although one can still certainly argue that this approach is entirely appropriate for the safety of patients, accumulating data seem to weaken this argument. With the increasing emphasis on “personalized medicine,” one wonders how drugs will be reasonably tested for safety and efficacy in the setting of ever smaller patient groups defined by more precise genotypes. Given the imprecise results of many animal efficacy and toxicity studies, as pointed out in this issue of Molecular Therapy, emphasis on animal studies is clearly a double-edged sword that is proving to be blunt rather than sharp as a safety tool.