Title : Humanized chimeric animals to test drugs or evaluate novel cell and gene therapies
Abstract:
Advances in preclinical models have allowed the creation of animals with genetic alterations that tolerate xenogeneic transplants of human hepatocytes. Over time, the loss of native (murine) hepatocytes is replaced by human cells leading to a “humanization” process of the liver. Such chimeric mice have served as final proof in preclinical studies where gene therapies (e.g., CrispR-Cas technology) or advanced cell treatments have been tested to correct congenital disorders. Our laboratory has pioneered the use of cell therapy to treat patients with liver disease. However, for preclinical studies, many small animal models of monogenetic liver disease do not faithfully recreate the phenotype observed in human patients. Using a special FAH-deficient and immune-compromised mouse, we have generated new human-relevant models. Hepatocytes isolated from normal donors or patients undergoing liver transplants due to inborn errors of metabolism were transplanted into the murine liver, replacing 85-95% of the mouse hepatocytes with human hepatocytes, as quantified by plasma human albumin levels. Mice repopulated with normal hepatocytes displayed normal hepatic functions including ammonia levels, while mice repopulated with hepatocytes deficient for one specific liver enzyme displayed increased basal levels of ammonia or other systemic alterations characteristics of donor disease. Such new preclinical models are extremely useful for investigations of the disease process, in vivo, and for possible corrective interventions such as gene or cellular therapies. When the strengths and weaknesses of these humanized mouse models are fully understood, they will likely be quite valuable for investigations of human liver-mediated metabolism and excretion of drugs and xenobiotics, patient-specific pharmacological effects, and short- and long-term investigation of the toxicity of drugs or chemicals with significant human exposure. Finally, the effective and functional maturation of stem/progenitor cells isolated or engineered using the most advanced techniques has in this model the final validation.
Audience Take away:
- I will provide a brief overview on novel preclinical models and their use in cell-based therapies for liver disease
- List all other benefits.
- Cell-based therapies are gaining recognition and importance as an alternative treatment to solid organ transplantation. Immunosuppression and short-term effects are currently the major limitations to expanding such applications. We have studied and developed solutions to circumvent such roadblocks and offer
