Current pre-clinical animal models may not accurately reflect human drug absorption, distribution, metabolism, and excretion (ADME) and toxicity, leading to a great deal of drug failures. Hera is developing “humanized” rodent models and screening services which will give toxicologists and pharmacologists confidence in their ADME-Tox findings, drug safety assessments and may prevent drug failures. For example, as one recent study showed, humanized liver mice could have predicted liver toxicity and prevented a failed clinical trial that led to the death of 5 patients by an investigational hepatitis B drug known as fialuridine (FIAU) (link to applications page)
Hera is humanizing model organisms, such as rat and mouse, in two ways: tissue or cellular humanization and genetic humanization. Tissue or cellular humanization involves replacing cells or entire organs with human cells in order to develop a functioning human liver or immune system within the model organism. This type of humanization must be done in an immunodeficient or “SCID” animals so that it does not reject the transplanted human cells. Another approach is to replace particular endogenous genes, such as the Cyp2d, which are is involved in drug metabolism, with their human orthologs.
It is desirable to evaluate the metabolism of candidate pharmaceuticals in primary fully mature human hepatocytes in vivo because the liver is the key organ for metabolism of xenobiotics and many hepatic enzymes are species specific. One of the major roadblocks for testing new drug candidates is the limited availability of human hepatocytes and the inability of stem cell-derived hepatocytes to fully mature in vitro, and therefore the inability to human test for specific metabolites. Our liver humanized models program will provide a solution with a potentially unlimited source of fully differentiated mature human hepatocytes.
Hera is focused on the creation of humanized mice and rats for ADME-Tox studies. In particular we will utilize our unique ability to engineer rat models as it is the preferred rodent model in pre-clinical drug studies because their larger size facilitates procedures otherwise difficult in mice, including studies using instrumentation, blood sampling, and surgeries, and allows for ten times the amount of tissue collection per animal. In addition, rat models are superior to mouse models for testing the pharmacodynamics and pharmacokinetics (PK/PD) and toxicity, partially because many of their detoxifying enzymes are very similar to those in humans.