IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia - PROJECT SUMMARY
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), (2),
(3). 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 (4), (5, 6), (7), (8). 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.
Specific Aim I: Dose and Dose Frequency Optimization, ADME, Multi-dose PK/PD, Target Engagement
Specific 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).
