PROJECT SUMMARYVascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementias(ADRD) significantly contribute to the 55 million people world-wide who suffer with dementia. This number isestimated to increase to over 139 million people by 2050 (WHO). A number of studies have shown that VCID andconversion to ADRD are strongly correlated with vascular disease inflammation and decreased cerebral brainblood flow 123 456 78. The relationship between vascular disease cognitive function and progression todementia and possible AD have been recently reviewed 9. These authors successfully make the case for a closerelationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore conversion rates ofVCI to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCI 1011. There is anurgent unmet medical need for therapeutics to prevent cognitive decline in individuals at risk for VCID.The goal of this proposed late-stage NIA U01 ADDP program is to complete FDA-required long-term toxicologyand safety studies required to advance to a Phase 2 clinical trial of the anti-inflammatory peptide PNA5 fortreatment of persons with MCI and are at risk for VCID/ADRD. The peptide PNA5 is a novel pleotropic anti-inflammatory Angiotensin-(1-7)/MasR agonist that has outstanding brain penetration enhanced bioavailabilitydecreases brain and cerebrovascular inflammation improves cerebral blood flow and restores cognitive functionin our preclinical VCID model 12131415. None of the other published studies with oral formulations of Ang-(1-7)related peptides or small molecules 181920 have exhibited the excellent brain penetration that we have observedwith our glycosylated peptides which will be key for developing an effective CNS anti-inflammatory cognitiveprotective therapeutic. With support from the NIA we are completing our early stage ADDP program havesuccessfully completed our FDA pre-IND meeting and will have our new FDA IND for PNA5 by Q3 2023. By thetime of this review we will have completed our formal initial 28-day toxicology and safety work for PNA5 requiredfor Phase 1a first-in-human safety studies. In this application we are requesting support for 1) additional long-term exposure safety analysis2) expanded GMP manufacturing and final formulation and packaging for a Phase2 trial and 3) FDA regulatory documentation and design of the Phase 2 trial required to advance to Phase 2clinical trials in persons with MCI at risk for VCID/ADRD.Specific Aim I: Conduct six-month chronic toxicology studies in two species to determine the toxicokinetic andsafety profiles for subcutaneously administered PNA5.Specific Aim II. Expanded GMP manufacturing and final fill and finish of PNA5 for Phase 2 trials in VCID.Specific Aim III: Complete regulatory assessments and documentation for submission to FDA and togenerate Phase 2 clinical trial design and plan.