Formulation of a Novel Therapeutic for Treating Cognitive Impairment in Patients at-risk for Alzheimer's Disease-Related Dementias and Vascular Contributions to Cognitive Impairment

血管对认知损害和痴呆(VCID)和阿尔茨海默病相关痴呆的贡献 (ADRD)对全球4700万痴呆症患者做出了重大贡献。这个号码是 预计到2050年将增加到超过1.3亿人。多项研究表明，VCID和 转换为ADRD与血管疾病、炎症和脑功能减退密切相关 血流(1)、(2)、(3)、(4)、(5)、(6)、(7)、(8)。血管疾病与认知功能的关系 最近回顾了进展为痴呆症和可能的阿尔茨海默病(9)。这些作者成功地制作了 心血管危险因素与VCID和ADRD的风险密切相关。此外， 据报道，在被诊断为VCI的5年内，VCI转化为痴呆症的比率在40%-46%之间 (10)、(11)。到目前为止，还没有批准的治疗VCID的方法。ProNeurogen一直致力于开发新的 血管紧张素-1-7(Ang-1-7)制剂治疗高危患者炎症相关认知功能障碍 ADRD和VCID。目前SBIR第一阶段项目的目标是开始可行性研究，以开发 用于给药的新型多肽的缓释皮下注射制剂 治疗与脑炎症相关的认知障碍和VCID的疗法。这些新的多肽 制剂设计用于作用于脑血管内皮细胞和神经元中的mas受体(MASR) 细胞和小胶质细胞，以减少脑内ROS的产生和神经炎症。我们已经开始翻译这些 新型多肽疗法治疗炎症性认知障碍的临床前研究 有ADRD或VCID风险的心脏病患者。我们有批准的FDA IND#125320，并支持 国产血管紧张素-(1-7)治疗心力衰竭患者和国立卫生研究院认知障碍的2a期试验 支持我们在心脏搭桥手术患者(CABG)中的试验。我们目前批准的治疗方案 HF/VCID患者每天一次，皮下注射100微克/公斤，使用标准针头和注射器治疗 我们的VCID/HF患者85天。然而，为了提高患者的依从性，以及加快 商业化我们目前正在研究更有利于患者的新配方，并需要 更少的注射。我们将利用Oakwood Labs在扩展版本方面的丰富经验 配制无菌注射剂，以完成本项目的两个主要目标： 1.目标1.完成开发缓释皮下注射制剂的可行性研究 Ang-(1-7)。 2.目的2.缓释注射剂型的体内比较PK研究 在成功完成这些可行性研究后，我们将在第二阶段进行广泛的PD PLGA-Ang-(1-7)在我们的VCID动物模型中建立认知功能的研究 PLGA-Ang-(1-7)的保护和脑抗炎作用并最终启动IND 学习。

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. A number of studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow (1),(2),(3), (4),(5),(6), (7),(8). The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed (9). These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCI to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCI (10),(11). 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 inflammation-related cognitive impairment in patients at for risk ADRD and VCID. The goal of the present SBIR Phase I project is to begin feasibility studies to develop an extended release subcutaneous injection formulation for the administration of our novel peptide therapies to treat brain inflammation related cognitive impairment and VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium and neuronal cells and microglia to decrease brain ROS production and neuroinflammation. 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). Our current approved treatment protocol for HF/VCID patients is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days in our VCID/HF patients. However, in order 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 Oakwood Labs’ extensive experience with extended release formulation of sterile injectables to complete the 2 principal objectives of this project: 1. Objective 1. Complete feasibility studies to develop extended release subcutaneous injection formulation of Ang-(1-7). 2. Objective 2. Complete comparative in vivo PK studies of the extended release injection formulations. Following successful completion of these feasibility studies, in Phase II we will conduct extensive PD studies of the PLGA-Ang-(1-7) formulation in our VCID animal model to establish the cognitive protective and brain anti-inflammatory effects of PLGA-Ang-(1-7) and ultimately begin IND enabling studies.