PROJECT SUMMARYIn the proposed early stage NIA U01 ADDP program we will: 1) finalize dose-optimization of our lead compound2) complete PK/PD testing and 3) begin manufacturing formulation and the toxicological and safety analysesrequired to advance our lead compound to IND submission and clinical studies for patients at risk for VascularContributions to Cognitive Impairment and Dementia (VCID) and conversion to Alzheimers Disease and RelatedDementias (ADRD). Our vision is to be a first-in-class therapy to reduce inflammatory-disease relatedcognitive impairment and inhibit dementia development in patients at risk for VCID and ADRD. We willleverage our experience with our currently approved FDA IND # 125320 and ongoing trials for the use of nativeAng-(1-7) treatment of cognitive impairment in patients with heart failure (HF) or cardiac disease to advance our2nd-generation glycosylated Ang-(1-7) to complete full regulatory toxicology needed for IND submission andPhase I safety studies. Our comprehensive University of Arizona and ProNeurogen team of peptide medicinalchemists neuroscientists pharmacologists and drug industry specialists have developed a novel approach totake advantage of the anti-inflammatory and neuroprotective nature of the G-protein linked Mas receptor andour extensive experience with Ang-(1-7) agonists. Within the brain the Mas receptor is expressed on neuronsmicroglia and vascular endothelial cells and activation of Mas decreases ROS and brain inflammation increasescerebral circulation via increases in endothelial NO release and inhibits hypoxia-inducing factor-1alpha (1) (2)(3). Our research team has developed optimized and completed high-throughput in vitro and in vivo screensof novel synthetic glycopeptide derivatives of Ang-(1-7) that have outstanding brain penetration and enhancedstability (4) (5 6) (7) (8). We have completed full physiochemical profiling of our lead candidate. With thecompletion of the Aims below we will obtain the protocols and necessary documentation to file a new IND withthe FDA to begin clinical trials for cognitive impairment in patients as risk for developing VCID or ADRD.Specific Aim I: Dose and Dose Frequency Optimization ADME Multi-dose PK/PD Target EngagementSpecific Aim II. Scale up synthesis. GMP manufacturing and formulation of our final lead glycosylated Ang(17) compound will be synthesized by our CRO PolyPeptide Group. (Completed by CRO)Specific Aim III Regulatory Toxicology Studies (Completed by CRO).Specific Aim IV: IND Preparation and Submission (UA and FDA regulatory consultant).