In the proposed early stage NIA U01 ADDP program, we will: 1) finalize dose-optimization of our lead compound, 2) complete PK/PD testing and, 3) begin manufacturing, formulation and the toxicological and safety analyses required to advance our lead compound to IND submission and clinical studies for patients at risk for Vascular Contributions to Cognitive Impairment and Dementia (VCID) and conversion to Alzheimer's Disease and Related Dementias (ADRD). Our vision is to be a first-in-class therapy to reduce inflammatory-disease related cognitive impairment and inhibit dementia development in patients at risk for VCID and ADRD. We will leverage our experience with our currently approved FDA IND # 125320 and ongoing trials for the use of native Ang-(1-7) treatment of cognitive impairment in patients with heart failure (HF) or cardiac disease to advance our 2nd-generation glycosylated Ang-(1-7), to complete full regulatory toxicology needed for IND submission and Phase I safety studies. Our comprehensive University of Arizona and ProNeurogen team of peptide medicinal chemists, neuroscientists, pharmacologists and drug industry specialists have developed a novel approach to take advantage of the anti-inflammatory and neuroprotective nature of the G-protein linked Mas receptor and our extensive experience with Ang-(1-7) agonists. Within the brain, the Mas receptor is expressed on neurons, microglia and vascular endothelial cells and activation of Mas decreases ROS and brain inflammation, increases cerebral circulation via increases in endothelial NO release and inhibits hypoxia-inducing factor-1alpha 1,3,17. Our research team has developed, optimized and completed high-throughput in vitro and in vivo screens of novel synthetic glycopeptide derivatives of Ang-(1-7) that have outstanding brain penetration and enhanced stability 2,4,6,10,12. We have completed full physiochemical profiling of our lead candidate. With the completion of the Aims below, we will obtain the protocols and necessary documentation to file a new IND with the FDA to begin clinical trials for cognitive impairment in patients as risk for developing VCID or ADRD. The diversity supplement will focus on Specific Aim of the parent application with a focus on the inclusion of menopausal females. The pertinent specific hypothesis that will be directly addressed by the supplement candidate is as follows: Hypothesis. The glycosylated Ang 1-7 peptide (PNA5) will significantly improve bio-availability of Ang 1-7 and increase PNA5 concentration in the brain, in menopausal females, with little to no BBB disruption, who demonstrate VCID cognitive impairment via activation of the G-protein linked Mas receptor. Accordingly, to address the specific hypothesis, the following Specific Aims will be executed:
Aim I a. Identify Minimal Effective Dose (MED), Optimal Effective Dose (OED) and Optimal Dose Frequency for native Ang-(1-7) and PNA5 for cognitive protection in menopausal females.
Aim I b. Assess and compare ADME and PK for native Ang-(1-7) and PNA5 in menopausal females.
Aim I c. Target Engagement and Biomarker Inflammatory Assay in menopausal females.
Our vision is to advance our glycosylated-Angiotensin 1-7 as a first-in-class therapy to reduce inflammatory- disease related cognitive impairment in patients at risk for Alzheimer's Disease and Related Dementias (ADRD) and Vascular Contributions to Cognitive Impairment and Dementia (VCID). With the completion of this project we will obtain the protocols and necessary documentation to obtain an IND for our peptide to begin clinical trials to treat cognitive impairment due to cardiovascular disease in patients as risk for developing ADRD and VCID.
