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The class of compounds known as korupensamines exhibit in vitro and in vivo antimalarial activity and offer a potent new means for treating and controlling this devastating disease. As many as 2-3 million people worldwide die from malaria each year, and many more suffer from long-term chronic infection. The deadliest malarial parasites have become resistant to previously effective antimalarial drugs such as chloroquine and other clinically useful agents; therefore, effective new antimalarial drugs are urgently needed. These korupensamine compounds, which are isolated from a new species of the plant genus Ancistrocladus which is found in tropical Africa and southern and southeast Asia, effectively inhibit the growth, reproduction, and pathologic effects of a broad spectrum of Plasmodia parasites when given alone or in conjunction with previously available antimalarial agents. Licensees of this invention will be required to comport with all applicable federal and country-of-collection policies relating to biodiversity.
The invention provides a synthetic gene encoding an allelic fonn of non-glycosylat~d Plasmodium falciparum Apical Membrane Antigen 1 optimized for codon usage in Pichia pastoris (e.g., AMAI FVa and AMAI 3D7); the subsequent transfonnation of Pichia pastoris with this gene, the separate optimization for pH, temperature, growth rate, and media composition of reproducible, scalable, clinical grade fennentation conditions for the expressionof the products of the gene; a method of purification for de-lipidation to clinical grade purity of the products of the gene; and proof of efficacy of the purified protein products in in vitro growth inhibition assays and in vivo non-human primate challenge models. Expression, Purification And Efficacy testing of Synthetic Plasmodium Falciparum Apical Membrane Antigen 1 Expressed in Pichia Pastoris Two recombinant forms of the malaria asexual blood stage antigen Apical Membrane Antigen 1 AMA1 were produced in Pichia pastoris using totally defined, synthetic medias and a fermentation methodology that has been reproducibly scaled over a 10-fold range to 60L. High levels of secreted recombinant protein were obtained 300mg/L secreted protein in the supernatant, and >50mg/L final purified bulk protein , and a purification strategy developed to remove Host cell-derived lipids. Highly purified forms of both types of AMA1 produced appear to produce antibodies in vivo in rabbits that block homologous parasites from invading red blood cells in vitro. The combination of the two allelic forms made appears potent at inducing antibodies capable of blocking the invasion of many heterologous parasite strains in vitro, suggesting that the combination of these two alleles of AMA1 will provide sufficient coverage from the diverse field populations of parasites. One of the two AMA1's, based on the FVO allelic variant of AMA1, was emulsified with complete and incomplete Freund's adjuvant. Vaccination of highly susceptible Aotus vociferansmonkeys with this formulation conferred significant protection from a subsequent lethal challenge with the virulent FVO Plasmodium falciparumparasite. Five of eight animals whose primary immune response was directed against AMA1 were completely protected. These two recombinant forms of AMA1 may be an effective malaria vaccine. The production and purification methodologies may be suitable to other therapeutic proteins where large-scale, inexpensive production methodologies are required.
The invention pertains to full-length polypeptides and fragments from naturally occurring Merozoite Surface Protein 1 (MSP-1; a protein expressed in later stage erythrocytic malaria) including vectors having encoding nucleic acids thereof that are useful as DNA vaccines. The intent was that the MSP-1 proteins expressed through these vectors would generate protective immune responses against subsequent infection by Plasmodium falciparum, the pathogen responsible for malaria.
Synthetic genes for malarial proteins and methods of use Synthetic gene sequences encoding erythrocyte binding protein of a malaria pathogen for the expression of the erythrocyte binding protein. The codon composition of the synthetic gene sequences approximates the mammalian codon composition. The synthetic gene sequences are useful for incorporation into the DNA vaccine vectors, for the incorporation into various expression vectors for production of malaria proteins, or both. The synthetic genes may be modified to avoid post-translational modification of the encoded protein in hosts. Administration of the synthetic gene sequences, or the encoded protein, as an immunization agent is useful for induction of immunity against malaria, treatment of malaria, or both.
Compositions that inhibit the binding of Plasmodium falciparum to erythrocytes include a family of erythrocyte binding proteins EBPs. The EBPs are paralogues of the P. falciparum binding protein EBA-175. The present invention includes peptides of the paralogues that prevent the binding of P. falciparum. Antibodies specific for each paralogue that also prevent the binding of P. falciparum are included. Methods of the invention utilize the paralogues, antibodies thereof and peptide compositions for the diagnosis, prevention, and treatment of P. falciparum diseases such as malaria, as well as methods for the detection of P. falciparum in biological samples and culture media.
Wucheria bancrofti, the major causative organism of lymphatic filariasis, is a filarial nematode estimated to infect 120 million people worldwide. The World Health Organization has targeted this disease for eradication. Current technology fails to recognize prepatent infections so there is a strong need for this technology in eradication efforts. This immunologically based assay detects Wuchereria bancrofti infection with no cross reactivity with other closely related filariae.