Extended-Release Formulation of Mas Receptor Agonists as Novel Therapeutics for Treating Cognitive Impairment in Patients at-risk forAlzheimer's Disease-Related Dementias and Vascular Dementia

Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease related dementias (ADRD) significantly contribute to the 47 million people world-wide who suffer with dementia. This number is estimated to increase to over 130 million people by 2050. Several studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow. The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed 1. These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCID to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCID. To date, there are no approved therapies for VCID. ProNeurogen has been working to develop novel Angiotensin 1-7 (Ang-1–7) formulations to treat cognitive impairment in patients at for risk ADRD and VCID. The goal of the present SBIR Phase I project is to advance the development of extended-release (ER) subcutaneous injection formulation for the administration of our novel peptide therapy, PNA5, for VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium, neuronal cells and microglia to decrease brain reactive oxygen (ROS) production and neuroinflammation. We have begun to translate these preclinical findings into novel peptide therapeutics to treat cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. With support from NIA, we are currently completing our formal IND enabling toxicology studies required to advance PNA5 to human clinical trials for VCID and expect to submit our IND application by Q1 2023. Our current planned treatment protocol for VCID patients is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days. However, to increase patient compliance as well as accelerate commercialization we are currently investigating new formulations that are more patient friendly and require fewer injections. We will take advantage of Drug Delivery Experts LLC (now Pace Labs) extensive experience in the formulation of poly(lactic-co-glycolic acid) (PLGA) sterile injectable in-situ gel formulations and manufacturing expertise to complete the 2 principal objectives of this project. Objective 1: Complete formulation development and scale up batch manufacturing of our extended- release in-situ gel injection formulation of PNA5. Objective 2. Complete in vivo PK studies of the extended-release injection formulations and compare to standard saline formulations of PNA5. Following successful completion of these feasibility studies, in Phase II we will conduct extensive PD/PK studies of the PNA5-PLGA formulation in our VCID animal model to establish the cognitive protective and anti- inflammatory effects of PNA5-PLGA and begin formal toxicology IND enabling studies.