Use of Genetically Engineered Mice in Drug Discovery and Development: Wielding Occam's Razor to Prune the Product Portfolio

Abstract

Genetically engineered mice (GEMs) that either overexpress (transgenic) or lack (gene-targeted, or "knock-out") genes are used increasingly in industry to investigate molecular mechanisms of disease, to evaluate innovative therapeutic targets, and to screen agents for efficacy and/or toxicity. High throughput GEM construction in drug discovery and development (DDD) serves two main purposes: to test whether a given gene participates in a disease condition, or to determine the function(s) of a protein that is encoded by an expressed sequence tag (EST, an mRNA fragment for a previously uncharacterized protein). In some instances, phenotypes induced by such novel GEMs also may yield clues regarding potential target organs and toxic effects of potential therapeutic molecules. The battery of tests used in phenotypic analysis of GEMs varies between companies, but the goal is to define one or more easily measured endpoints that can be used to monitor the disease course--especially during in vivo treatment with novel drug candidates. In many DDD projects, overt phenotypes are subtle or absent even in GEMs in which high-level expression or total ablation of an engineered gene can be confirmed. This outcome presents a major quandary for biotechnology and pharmaceutical firms: given the significant expense and labor required to generate GEMs, what should be done with "negative" constructs? The 14th century philosophical principle known as Occam's razor-that the simplest explanation for a phenomenon is likely the truth-provides a reasonable basis for pruning potential therapeutic molecules and targets. In the context of DDD, Occam's razor may be construed to mean that correctly engineered GEMs lacking obvious functional or structural phenotypes have none because the affected gene is not uniquely essential to normal homeostasis or disease progression. Thus, a "negative" GEM construct suggests that the gene under investigation encodes a ligand or target molecule without significant therapeutic potential. This interpretation indicates that, at least in a market-driven industrial setting, such "negative" projects should be pruned aggressively so that resources may be redirected to more promising DDD ventures.

Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Novel Pharmaceuticals

“…3, 2013 USE OF ANIMAL MODELS OF HUMAN DISEASE 515 standard nonclinical toxicity studies in healthy animals. Animal models of disease rarely, if ever, accurately recapitulate all the key aspects of the corresponding human disease, may have inconsistent disease manifestations, and are less wellcharacterized toxicology models than standard models utilizing healthy animals (Bolon and Galbreith 2002;Cordaro 1989). Thus, targeted animal models are typically inappropriate to use in general toxicity studies that include complete evaluation of clinical and anatomic pathology endpoints.…”

Mendelian Randomization in the Era of Genomewide Association Studies

“…The most clear-cut example of developmental compensation is from the study of knock-out animals, in which a functional gene is effectively removed from the study organism. The anticipated consequence of such a removal would be strong phenotypic effects, which, in fact, are not always apparent because of a compensatory mechanism built into the biological system (36,37 ). For example, myoglobin is known to be crucial for heart function in mice, but the knock-out model animal experiences no disruption in cardiac function (38 ).…”

Functional genetic mouse models: promising tools for investigation of the proteolytic internet

“…In this case, one can conclude that the missing gene has a rather direct function in the affected physiology and no compensation by other genes had occurred. According to the 14th-century philosophical principle known as Occam's razor -that the simplest explanation for a phenomenon is likely the truth -this group serves well in the definition of drug targets (Bolon and Galbreath, 2002). The second group is represented by surviving mice with an obviously healthy phenotype, which means that the missing gene was compensated and a new homeostasis had been established.…”

“…Functional genetic mouse models with specific overexpression or total lack of expression of genes have contributed to elucidation of their physiological functions as well as the pathological consequences induced by their deregulated expression (Bolon and Galbreath, 2002), and are the basis of many mouse carcinogenesis models under study (Frese and Tuveson, 2007). The branch of cancer research, however, which does not focus on tumorigenesis, but on unsolved problems of tumor cell dissemination and metastasis, is not as dependent on genetically engineered mice with an overt functional or structural phenotype: genetic modulation of the host tissue is already a sufficient experimental manipulation, as it is now recognized that the microenvironment is an important determinant in tumor progression and metastasis (Kulesa et al, 2006).…”