Methods for Immunization Or Treatment of Humans and Animals Against Viruses (HIV Including), Infectious Agents, Cancer and Other Genetically Treatable Maladies
Apicomplexan parasites are significant pathogens of humans and animals, and cause diseases such as toxoplasmosis, malaria, cryptosporidiosis, theileriosis, and many others. For these reasons various pharmaceutical companies are in the process of developing specific chemical reagents to inhibit these parasites, or various formulations which may confer immunity to these pathogens.
While the de novo pyrimidine biosynthetic pathway is believed to be essential for all apicomplexan parasites this has not been previously verified by genetic evidence. Researchers at Dartmouth have used the apicomplexan parasite Toxoplasma gondii to verify that the enzymes of the de novo pyrimidine biosynthetic pathway are essential. Dartmouth researchers cloned the first and key regulatory enzyme of this pathway, carbamoyl phosphate synthase II (CPSII), and developed a parasite strain with a disruption (knock-out) of the CPSII. The CPSII knock-out mutant is auxotrophic for pyrimidines (uracil) and it has no observable growth rate without pyrimidine supplementation of growth medium in vitro. These experiments show that the parasite CPSII is a novel drug target for Toxoplasma, and perhaps other apicomplexans. The CPSII knock-out mutant is extremely attenuated in mice (in vivo), showing at least a 7 log (10-million fold) attenuation compared to its parent strain. Remarkably, this mutant is just as highly attenuated in immune deficient mice as in immune competent mice, being the first mutant that is completely avirulent in gamma interferon knock-out mice. A single dose of the mutant confers long-term protective immunity to Toxoplasmosis.
This invention enables the researchers to use the CPSII cDNA to express large amounts of T. gondii CPSII in intact cells or cell free systems for the purpose of screening and testing for chemical agents serving as specific CPSII inhibitors to be developed for therapeutic prevention or treatment of Toxoplasmosis, or other diseases caused by apicomplexan parasites. Avirulent auxotrophic CPSII knock-out mutants should enable the researchers to examine the feasibility of using extremely attenuated T. gondii as a vaccine formulation.
The extreme avirulence, the genetic tractability and the unusual immunogenicity of this parasite make it an interesting experimental vaccine formulation for delivering immunity (or therapy) to various infectious agents, cancer, and any malady for which a vaccine or gene-based therapy may have efficacy.
These findings are claimed in the published Patent Corporation Treaty Application No. PCT/US01/03906. We are seeking an industrial partner who is interested in their further refinement and commercialization. (Ref: J123)
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