A growing body of evidence indicates that decreased brain blood flow, increased reactive oxygen(ROS) and pro-inflammatory mechanisms accelerate the progression of neurodegenerativediseases such as Alzheimer's Disease and Related Dementias (ADRD) including VascularContributions to Cognitive Impairment (VCID) 1, 2,3,4, 5. ProNeurogen has been working with ourUniversity of Arizona collaborators to develop novel Angiotensin 1-7 (Ang-1-7) formulations totreat inflammation-related cognitive impairment in heart disease patients at for risk ADRD andVCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within thebrain vascular endothelium and neuronal cells to decrease brain ROS production,neuroinflammation and improve cerebral vascular blood flow. We have begun to translate thesepreclinical findings into novel peptide therapeutics to treat inflammation related cognitiveimpairment in patients with heart disease who are at risk for ADRD or VCID. We have anapproved FDA IND # 125320 and support for Phase 2a trials for native Ang-(1-7) for treatment ofcognitive impairment in heart failure (HF) patients and NIH support for our trial in cardiac bypasssurgery patients (CABG). We are currently enrolling in these studies. Our current approvedtreatment protocol is once a day, subcutaneous 100 microg/kg injection using a standard needleand 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 increasepatient compliance as well as accelerate commercialization we are currently investigating newformulations and injection methods that are more "patient friendly" and will decrease the numberof injections required. We have recently completed feasibility studies and identified our leadextended-release Ang-(1-7) formulation (PNA1-ER) and are progressing towards IND submissionfor this new formulation. The goal of the present SBIR Phase I project is to 1) scale-up batchdevelopment of our extended-release poly (lactic-co-glycolic acid) (PLGA) in-situ gel formulationsfor subcutaneous injection of PNA1-ER, 2) begin formal PK and pharmacotoxicity studies ofPNA1-ER required for IND submission.Objective 1: Scale-up batch development of our lead candidate extended-release in-situ gelformulations for subcutaneous injection of Ang-(1-7) (PNA1-ER).Objective 2: Single-dose Pharmacokinetics and Local Tolerability Study of PNA1-ER inRats.Objective 3: Repeat-dose PK and Tolerability Study of PNA1-ER in Rats.
Public Health Relevance Statement: PROJECT NARRATIVE
Our vision is to advance our novel Angiotensin 1-7 peptides 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). The goal of the present Phase I
project is to scale up batch manufacturing begin IND enabling studies of our extended release formulation of
Ang-(1-7) peptide therapy for treating VCID.
Project Terms:
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