The objective of this proposal is to initiate in vivo studies examining use of antisense oligonucleotides (AS ODNs) as chemotherapeutic agents to control/prevent malarial infection. This disease afflicts over 200 million people world wide, and is becoming increasingly difficult to treat due to wide spread resistance to currently available anti malarial drugs. New anti malarial compounds are urgently needed. AS ODNs work by specifically inhibiting gene expression of the target protein. We have shown that AS ODNs directed against several different genes in the malarial parasite Plasmodium falciparum can inhibit growth in in vitro culture, and now seek to examine the efficacy of such compounds in vivo. Because P. falciparum infects only humans or some species of monkeys, our initial studies will utilize small animal model systems consisting of the non-human malarial species P. gallinaceum and P. berghei. Studies will examine the effects of dose, frequency and route of administration in controlling infection. Establishing efficacy in these systems will provide the basis for future studies on the human parasite in monkeys, which in turn will lead to human clinical trials.Proposed Commercial Applications:The world wide market for anti malarials is estimated between $200-300 million per year, yet increased drug resistance renders many compounds ineffective.
Thesaurus Terms:Plasmodium, antimalarial agent, antisense nucleic acid, drug design /synthesis /production, drug screening /evaluation, oligonucleotide Plasmodium berghei, Plasmodium falciparum, dihydrofolate reductase, pharmacokinetics chicken, laboratory mouse, nucleic acid chemical synthesis
