Humanized Rats: The Future of Drug Development
A key technique in modern medical research is transplantation of human immune system components into laboratory animals. However, modern molecular biology has made it possible to humanize animals at an even deeper level by transplanting human DNA.
This is precisely what one group of researchers did using the CRISPR/Cas9 system. CRISPR/Cas 9 is a relatively new technology that allows researchers to edit DNA by removing, adding, or altering sections of the DNA sequence. These researchers focused explicitly on transplanting the CYP1A2 gene, found mainly in the liver, from humans into rats. The CYP1A2 gene is important because it is responsible for metabolizing many common drugs, making them compatible with your body and fit for excretion. Predicting exactly how CYP1A2 will process certain drugs is crucial for drug development and dosage guidelines.
To transplant the human DNA, the researchers selected four target sites in the first exon (a region of a gene that gets transcribed to RNA) of the rat CPY1A2 gene. The target site sequence had to end with “GG” to be selected. These sites were cut out and replaced with the corresponding human DNA sequence using CRISPR/Cas9. The results showed that the CPY1A2 gene was successfully integrated into the rats without any statistical differences or physical symptoms compared to those who did not receive treatment.
In performing this treatment, this group of researchers created a generation of humanized CYP1A2 rats. This research is a significant step because rats can simulate almost all known human diseases. This specific study can lead to advancements in the field of pharmacokinetics (a branch of pharmacology concerned with the movement of drugs in the body). The use of CRISPR/Cas 9 in rats can aid in understanding the impact of our own genes and provide new research for drug discovery.
Post-transplantation, the researchers studied the effects of dosing the humanized rats with a drug called Clozapine. Clozapine is commonly used to treat the symptoms of schizophrenia. They found that Clozapine tended to be metabolized into something called Norclozapine, which is slightly different in its efficacy and characteristics in the body. This is just one of many discoveries that have been made using CRISPR/Cas9 technology.
