Scale-up Manufacturing and IND Enabling Studies of Extended-Release Formulation of Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Alzheimer's Disease-Related Dementias

越来越多的证据表明，大脑血流量减少，活性氧增加 (ROS)和促炎机制加速神经退行性变的进展 阿尔茨海默病和相关痴呆症(ADRD)等疾病，包括血管 对认知障碍(VCID)的贡献1、2、3、4、5。ProNeurogen一直在与我们的 亚利桑那大学的合作者开发新的血管紧张素1-7(Ang-1-7)配方以 治疗有ADRD和ADRD风险的心脏病患者的炎症相关认知障碍 VCID。这些新的多肽制剂旨在作用于体内的Mas受体(MASR) 脑血管内皮细胞和神经细胞减少脑组织ROS的产生， 神经炎症，改善脑血管血流量。我们已经开始翻译这些 新型多肽疗法治疗炎症相关认知功能的临床前研究 有ADRD或VCID风险的心脏病患者的损害。我们有一个 批准FDA IND#125320并支持2a期本地Ang-(1-7)治疗 心力衰竭患者的认知障碍和美国国立卫生研究院对我们体外循环试验的支持 手术患者(CABG)。我们目前正在进行这些研究。我们目前批准的 治疗方案是每天一次，用标准针头皮下注射100微克/公斤 在我们的心力衰竭患者中使用注射器85天。然而，长期服用Ang-(1-7) 保护认知功能的多肽需要在数月内注射。增加 患者遵从性以及加速商业化，我们目前正在研究新的 配方和注射方法更“患者友好”，并将减少数量 所需注射的数量。我们最近完成了可行性研究，并确定了我们的领先地位。 缓释剂Ang-(1-7)制剂(PNA1-ER)，并正在向IND提交 这一新配方。目前SBIR第一阶段项目的目标是1)扩大批量 聚乳酸-乙醇酸共聚物(PLGA)缓释原位凝胶制剂的研制 对于皮下注射PNA1-ER，2)开始正式的PK和药物毒性研究 提交IND需要PNA1-ER。 目标1：我们的主要候选缓释原位凝胶的放大批量开发 血管紧张素-(1-7)(PNA1-ER)皮下注射制剂。 目的：PNA1-ER单剂量药代动力学及局部耐受性研究 老鼠。 目的：研究PNA1-ER重复给药对大鼠的耐受性。

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.