Each group of animals will undergo surgery to place a minipump subcutaneously. Some of these animals will also have an intracerebral cannula connected to the minipump for drug delivery, while the others will have the drug delivered subcutaneously. After two to eight weeks of drug administration, groups may begin behavioral studies (procedure A, B, C, or D), which may occur as frequently as daily for up to 4 weeks, or twice weekly for up to 6 months. Some animals may undergo a second surgical procedure to replace the minipump after 4 weeks of delivery, to provide a total of 8 weeks of continuous drug administration. Some animals will be euthanized at intervals after drug delivery without further testing, while others will be euthanized following behavioral testing of up to 6 months. The maximum time from the start of studies to euthanasia will be 8 months.
Each group of animals will be administered drugs by various routes over the course of up to 3 months (see drug table). Following at least one week of drug administration, blood pressure samples will be collected using noninvasive methods. Once the drug administration period is completed (up to 3 months after starting), some animals will undergo a non-survival surgery procedure for surgical blood pressure sampling procedures at various times after the last drug dose. Other groups will be euthanized and tissues collected for further analysis. Time from start of drug administration to euthanasia will be no more than 1 year.
Project 1) Groups of animals will be inoculated with 5 different doses of Example Virus or vehicle, with or without the addition of Example Drug A, B, or C at the time of injection. After appearance of clinical disease, some animals will receive treatment with experimental agents D, E, F, or G over the course of up to 12 weeks. Other animals will receive vehicle alone or no treatment. At time points up to 24 weeks after initial inoculation, animals will be euthanized and tissues collected.
Project 2) Animals will undergo one of 4 surgical procedures (Procedure A, B, C, or D) followed by treatment with Example Drug A, B, or C at the time of surgery. Some animals will receive treatments with agents D, E, or F as detailed above, and euthanized at up to 2 years following initial surgery.
Project 3) Animals will be given medicated feed to induce gene expression for up to 10 weeks before inoculation with Example Virus with or without Example Drug A as described in Project 1. Over the following 6 weeks, clinical signs will be evaluated and animals euthanized at various time points for tissue analysis. Some animals will undergo non-survival procedure A to analyze immune reactions, after which they will be euthanized without recovery from anesthesia. Animals will be maintained for up to 15 months post-infection before euthanasia.
Animals will be purchased and euthanized for the postmortem collection of tissues. No other procedures will be performed.
Groups of animals will receive drug treatments by injection or in special feed for up to 8 weeks, after which they will be euthanized and tissues collected for further analysis.