A growing body of evidence indicates that decreased brain blood flow, increased reactive oxygen (ROS) and pro-inflammatory mechanisms accelerate the progression of neurodegenerative diseases such as Alzheimer’s Disease and Related Dementias (ADRD) including Vascular Contributions to Cognitive Impairment (VCID) 1, 2,3,4, 5. ProNeurogen has been working with our University of Arizona collaborators to develop novel Angiotensin 1-7 (Ang-1–7) formulations to treat inflammation-related cognitive impairment in heart disease patients at for risk ADRD and VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium and neuronal cells to decrease brain ROS production, neuroinflammation and improve cerebral vascular blood flow. We have begun to translate these preclinical findings into novel peptide therapeutics to treat inflammation related cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. We have an approved FDA IND # 125320 and support for Phase 2a trials for native Ang-(1-7) for treatment of cognitive impairment in heart failure (HF) patients and NIH support for our trial in cardiac bypass surgery patients (CABG). We are currently enrolling in these studies. Our current approved treatment protocol is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days in our HF patients. However, long-term administration of Ang-(1-7) peptides to protect cognitive function will require injections over multiple months. To increase patient compliance as well as accelerate commercialization we are currently investigating new formulations and injection methods that are more “patient friendly” and will decrease the number of injections required. We have recently completed feasibility studies and identified our lead extended-release Ang-(1-7) formulation (PNA1-ER) and are progressing towards IND submission for this new formulation. The goal of the present SBIR Phase I project is to 1) scale-up batch development of our extended-release poly (lactic-co-glycolic acid) (PLGA) in-situ gel formulations for subcutaneous injection of PNA1-ER, 2) begin formal PK and pharmacotoxicity studies of PNA1-ER required for IND submission. Objective 1: Scale-up batch development of our lead candidate extended-release in-situ gel formulations for subcutaneous injection of Ang-(1-7) (PNA1-ER). Objective 2: Single-dose Pharmacokinetics and Local Tolerability Study of PNA1-ER in Rats. Objective 3: Repeat-dose PK and Tolerability Study of PNA1-ER in Rats.