Preclinical in vitro and in vivo toxicology evaluation is a critical step in pharmaceutical drug development. Unexpected issues with ADME or toxicity account for 50-60% of drug development program failures. Safety assessment issues and risks for humans are identified through hepatotoxicity, genotoxicity, immunogenicity, general toxicology, renal toxicity and secondary drug metabolite pharmacology studies.

Although traditional animal and cell models can simulate human disease they never fully mirror all aspects of human immune response or pathophysiology of disease. New more clinically relevant models can be created utilizing gene editing technologies. For example, genetic engineering can be used to create a rat with a humanized immune system. Rats are engineered to be immunodeficient and therefore can accept and develop a human immune system.  Applications of humanized immune system rats include immunogenicity and cytokine release (cytokine storm) studies.

Neurotoxicity is caused by drugs or chemicals that alter the normal activity of central nervous system (CNS). It has been demonstrated that gene mutations are associated with an increasing number of neurodegenerative syndromes, such as Alzheimer’s, Parkinson’s. With no optimal model system to determine the neurotoxic potential of compounds; there is a compelling unmet need for in vitro models and endpoint assays that are cost-effective, accurate, predictive, and sensitive that would also be amenable to high throughput screening. Gene edited cell lines that harbor mutations associated with disease states (disease and patient specific) as well as toxicity reporter cell lines may meet this unmet need in neuroscience R&D.

Hepatotoxicity, or drug induced liver injury (DILI) , is another spotlight for drug toxicity risk assessment.  Traditional models include primary hepatocyte or animal models for preclinical metabolism and toxicity testing. These assays frequently are not predictive for humans, as is clear from the number of high profile pharmaceuticals withdrawn from clinical trials or from the market after billions of dollars in drug development costs [e.g., Drug induced liver injuries (DILI) after Parexel, Renovis, Ketek, Vioxx®, Bextra, Pemoline, Bromfenac, or Troglitazone treatment]. The creation of rat models with humanized livers, generated by transplantation of either human stem cell-derived or primary hepatocytes, would provide valuable resources to assess the physiological effects of drug metabolites in the whole animal as well as human-specific DILI. In the long term, the ability to generate rats with humanized livers using cells from different donors would enable comprehensive testing of drug candidates in animal models that represent a diverse sampling of the human population. Humanized rats would therefore enable testing early in the developmental pipeline that can quickly identify and be used to address potential toxic metabolites to help speed up and lower costs of drug development.