DEVELOPMENT OF TOLL-LIKE RECEPTOR AGONISTS AS NEUROPROTECTANTS IN BRAIN ISCHEMIA

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Toll-Like Receptor (TLR) signaling can reprogram an inflammatory (injurious) response to stroke into a neuroprotective response in the brain. Agonists of TLRs 9 and 7 (CpG ODNs and imiquimod IMQ, respectively) are lead compounds for prophylactic neuroprotection against stroke. Clinical translational failures from rodent to human prompted additional preclinical evaluation. Using a primate stroke model we aim to establish essential effacy and pharmacokinetic data. Our preliminary studies support development of neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy with TLR9 (K-and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for the optimal drug in male NHP stroke model. Aim 3. Determine neuroprotective efficacy as prophylactic therapy in aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal drug as prophylactic stroke therapy in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles. Aim 7. Submit an IND application for the optimal candidate based on efficacy, pharmacokinetics and toxicity. Progress: Aim 1 studies are near completion, although the blinded study design, while optimal, prevents any preliminary analysis of the data collected so far.