Discovery of Antimalarial Drugs Using Humanized Pseudo-Liver Immunodeficient Mouse Model
Abstract
This research project addresses the Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area of malaria. Malaria is a disease caused by human plasmodium parasites. The two most important types are Plasmodium falciparum and Plasmodium vivax as they cause the greatest illness and death worldwide. One of the oldest drugs available to treat malaria is a drug called primaquine. Primaquine is a member of a class of drugs called 8-aminoquinolines. Primaquine treats the liver stage of malaria infection and will cure relapsing malaria. In fact, 8-aminoquinolines are the only class of molecules that cure relapsing malaria. However, there are some challenges with the widespread use of 8-aminoquinolines such as primaquine. The first is that drug causes hemolytic anemia, which is characterized by a temporary loss of circulating red blood cells. This occurs only in people with a genetically inherited mutation call Glucose Phosphate 6 dehydrogenase (G6PD) deficiency. The second challenge is that some people are not able to metabolize primaquine into its active form and because of that primaquine doesn t work. Despite these limitations, the 8 aminoquinolines remain an important class of antimalaria drugs if a compound can be developed that overcomes these limitations. We have been working on antimalaria drug development and focusing on 8-aminoquinolines that can circumvent these challenges. A key piece of drug development is having preclinical models that mimic human diseases. As part of that work, we have developed an animal model to test for hemolytic toxicity. In this model, human red blood cells from people with the G6PD deficiency are transfused into a mouse that has no functional immune system. Because the mice don t have an immune system, they cannot reject the red blood cells. When these mice are given primaquine, we can measure the loss of circulating human red blood cells. Thus, we have accomplished the validation and development of an important model that uses human cells. The next model that we need to develop is one that has models human Plasmodium infection. Historically, preclinical models have been either infection of monkeys or mice with similar Plasmodium species that infects those animals. However, because of the genetic differences between human and mouse or monkey Plasmodium species, questions remain as to whether these preclinical models accurately reflect drug sensitivity of the human Plasmodium parasites. Using our immunodeficient mice that can accept human tissue, we have injected human liver cell line into the mice. This cell line forms a tumor, which we are calling a pseudo-human liver in the mouse. The pseudo-human liver was then infected with Plasmodium falciparum. If we can validate this model, then we will have a humanized mouse model to test whether new antimalaria drugs are efficacious against human parasites. This grant proposes to first validate the infection of the pseudo-human liver with Plasmodium falciparum. This brings us closer to human relevancy in a mouse model system. Then we will test new 8-aminoquinoline analogs in a testing scheme that includes both our model for hemolytic toxicity and our model for efficacy. If we are successful, we will have identified a new 8-aminoquinoline that works for people who can t activate primaquine and for individuals that have a G6PD deficiency.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1620027
Entities
People
- Rosemary Rochford
Organizations
- United States Army
- University of Colorado Denver