Human adenoviruses (Ads) are a significant problem in immunosuppressed humans, especially in children undergoing allogeneic stem cell transplants. About 20% of these pediatric patients develop disseminated Ad infections and about half of the patients die. There are no anti-viral drugs approved to treat these Ad infections. Cidofovir and ribavirin are used in some cases, but it is not known whether they are effective because they have not been studied in a systematic controlled manner. Development of anti-Ad drugs has been hindered because there is no animal model for replicating human Ads. This is because Ads are highly species-specific. We are developing the Syrian hamster as a tumor model to study the efficacy, replication, toxicity, and biodistribution of oncolytic Ad vectors. We showed that human Ad serotype 5 (Ad5) and Ad5-based oncolytic vectors replicate well in hamster tumors, livers, lungs, and other organs following intratumoral or intravenous injection. Of great interest, immunosuppression of the hamsters using cyclophosphamide (CP) leads to much higher levels of replication of the viruses. Replication continues at high levels in tumors and livers for at least 42 days (the end of the experiment) following administration of the virus. Based on these observations, we propose to use CP-immunosuppressed Syrian hamsters as a new animal model to evaluate the efficacy and toxicology of anti-Ad drugs on disseminated Ad infections in immunocompromised patients. To obtain initial proof-of-principle for this model, we will evaluate the anti-Ad efficacy and toxicology of hexadecyloxypropyl-cidofovir (HDP-CDV).
In Specific Aim 1 we will examine HDP- CDV inhibition of Ad5 (a member of human Ad Species C) replication in the liver of hamsters immunosuppressed by CP. Ad5 replication in the liver and blood will be determined by qPCR, a tissue culture infectious dose assay 50 (TCID50 assay), and immunohistochemistry for an Ad virion protein. Toxicity will be assessed based on histopathology of the liver and serum chemistry.
In Aim 2 we will determine whether serotypes in human Ad Species A, B, D, E, and F replicate in the liver of hamsters immunosuppressed by CP. If they do replicate, then we will determine whether HDP-CDV inhibits their replication in cultured cells. ? ? When humans become severely immunosuppressed, for example when children with leukemia have their immune system destroyed by immunosuppressed drugs prior to receiving bone marrow stem cell transplants, these patients often develop systemic infections with different viruses. These infections, which may be due to new infections or to activation of latent viruses, occur because the patient's immune system cannot keep the virus in check. Adenoviruses are one of the types of viruses that cause these infections, and the infections frequently result in the death of the patient. Unfortunately, no anti-adenovirus drugs have been examined in controlled clinical trials, and therefore no drugs are approved to treat these adenovirus infections. One reason that clinical trials for anti-adenovirus drugs have not been conducted is because there is no suitable animal model available to test the effectiveness and toxicity of such drugs. In this grant application, we propose to develop the Syrian hamster as an immunosuppressed animal model to evaluate anti-adenovirus drugs. Success in this project could lead to the eventual approval of drugs to treat adenovirus infections in immunosuppressed patients. ? ? ?
| Toth, Karoly; Spencer, Jacqueline F; Dhar, Debanjan et al. (2008) Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A 105:7293-7 |
