BRAIN AS TARGET FOR ANTISENSE PEPTIDE NUCLEIC ACID DRUGS

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DESCRIPTION: (Applicant's Abstract) The goal of the proposed research is to characterize in rat the pharmacokinetics and pharmacodynamics of three antisense polyamide ("peptide") nucleic acids (PNAs) directed toward three different proteins in rat brain: the neurotensin receptor subtype 1 (NTR1), the morphine receptor subtype (MOR1), and the serotonin transporter (SERT). The long term goal of this research is to develop PNAs as antisense and antigene drugs to treat a variety of diseases, especially those affecting brain. In different experiments, different PNAs (either in unlabeled or in radioactively-labeled or fluorescently-labeled forms) will be administereed to rats by intravenous, intraperitoneal, or oral routes. From measurement of concentrations of PNAs in blood over time, pharmacokinetic variables, including absolute bioavailability of PNAs by the oral route, will be determined. The kinetics of entry of these PNAs into brain (as well as other organs) and their distributions within the brain will also be determined by various techniques, including histological. The kinetics of entry into brain will be correlated with the time course for the onset of and the recovery from their functional effects from behavioral, physiological, biochemical, and molecular biological experiments. Behavioral studies will measure antinociception (NTR1 and MOR1); physiological studies, hypothermia (NTR1); biochemical studies, binding sites for NTR1, MOR1, and SERT, as well as brain levels of serotonin and its metabolite, and molecular biological studies, levels of mRNA for each targeted protein. This research represents the initial studies that might lead to viable antisense and antigene therapies for many types of diseases.