Extended-Release Formulation of Mas Receptor Agonists as Novel Therapeutics for Treating Cognitive Impairment in Patients at-risk forAlzheimer's Disease-Related Dementias and Vascular Dementia

Mas 受体激动剂的缓释制剂作为治疗阿尔茨海默氏病相关痴呆和血管性痴呆风险患者认知障碍的新型疗法

• 批准号: 10594875
• 负责人: Meredith Hay
• 金额: $ 49.98万
• 依托单位: PRONEUROGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10594875
• 关键词: Advanced Development; Agonist; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Angiotensins; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Arizona; Brain; Budgets; Cells; Cerebrovascular Circulation; Cerebrum; Characteristics; Clinical Trials; Cognitive; Consultations; Copyright; Data; Data Set; Databases; Dementia; Development; Diagnosis; Disclosure; Disease; Dose; Drug Delivery Systems; Exhibits; Feasibility Studies; Formulation; GTP-Binding Proteins; Gel; Glycolates; Glycopeptides; Goals; Heart Diseases; Human; Impaired cognition; In Situ; In Vitro; Inflammation; Injectable; Injections; Institution; Intellectual Property; Joints; Laws; Lead; Legal patent; Methods; Microglia; Modeling; Needles; Neurons; Online Systems; Oral; Ownership; Oxygen; Patients; Penetration; Peptides; Persons; Phase; Policies; Procedures; Production; Publications; Publishing; Reactive Oxygen Species; Reporting; Research; Research Personnel; Resources; Risk; Saline; Serum; Small Business Innovation Research Grant; Software Tools; Sterility; Subcutaneous Injections; Syringes; Therapeutic; Toxic effect; Toxicology; Translating; Treatment Protocols; United States National Institutes of Health; Universities; Vascular Dementia; Vascular Diseases; Vascular Endothelium; Vision; base; cardiovascular risk factor; cognitive function; commercialization; compliance behavior; data sharing; data sharing networks; design; efficacy study; experience; in vivo; innovation; invention; link protein; material transfer agreement; neuroinflammation; novel; novel therapeutics; peptide drug; pre-clinical; prevent; receptor; scale up; small molecule; subcutaneous; treatment planning; vascular cognitive impairment and dementia

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. Several studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow. The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed 1. These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCID to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCID. 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 cognitive impairment in patients at for risk ADRD and VCID. The goal of the present SBIR Phase I project is to advance the development of extended-release (ER) subcutaneous injection formulation for the administration of our novel peptide therapy, PNA5, for VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium, neuronal cells and microglia to decrease brain reactive oxygen (ROS) production and neuroinflammation. We have begun to translate these preclinical findings into novel peptide therapeutics to treat cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. With support from NIA, we are currently completing our formal IND enabling toxicology studies required to advance PNA5 to human clinical trials for VCID and expect to submit our IND application by Q1 2023. Our current planned treatment protocol for VCID patients is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days. However, 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 Drug Delivery Experts LLC (now Pace Labs) extensive experience in the formulation of poly(lactic-co-glycolic acid) (PLGA) sterile injectable in-situ gel formulations and manufacturing expertise to complete the 2 principal objectives of this project. Objective 1: Complete formulation development and scale up batch manufacturing of our extended- release in-situ gel injection formulation of PNA5. Objective 2. Complete in vivo PK studies of the extended-release injection formulations and compare to standard saline formulations of PNA5. Following successful completion of these feasibility studies, in Phase II we will conduct extensive PD/PK studies of the PNA5-PLGA formulation in our VCID animal model to establish the cognitive protective and anti- inflammatory effects of PNA5-PLGA and begin formal toxicology IND enabling studies.

血管对认知障碍和痴呆 (VCID) 以及阿尔茨海默病相关痴呆的影响 (ADRD) 对全球 4700 万痴呆症患者做出了重大贡献。 预计到 2050 年，这一数字将增加到超过 1.3 亿。多项研究表明，VCID 和转化 ADRD 与血管疾病、炎症和脑血流量减少密切相关。 血管疾病、认知功能与痴呆和可能的 AD 进展之间的关系 最近已被审查 1. 这些作者成功地证明了两者之间的密切关系 心血管危险因素以及 VCID 和 ADRD 的风险 此外，VCID 转化为痴呆的比率。 据报道，诊断 VCID 后 5 年内的发病率在 40-46% 以内。 迄今为止，尚无批准的药物。 ProNeurogen 一直致力于开发新型血管紧张素 1-7 (Ang-1–7) 制剂，以治疗 VCID。 治疗有 ADRD 和 VCID 风险的患者的认知障碍 目前 SBIR 第一阶段项目的目标。 旨在推进缓释（ER）皮下注射制剂的开发 我们的新型肽疗法 PNA5 是针对 VCID 设计的。 作用于脑血管内皮、神经元细胞和小胶质细胞内的 Mas 受体 (MasR)，减少 我们已经开始转化这些临床前研究。 研究发现新型肽疗法可治疗心脏病患者的认知障碍 在 NIA 的支持下，我们目前正在完成正式的 IND 毒理学研究。 将 PNA5 推进到 VCID 人体临床试验所需的研究，并预计在 2023年第一季度。我们目前计划的针对VCID患者的治疗方案是每天一次，皮下注射100微克/公斤 然而，为了提高患者的依从性，使用标准针头和注射器注射 85 天。 加速商业化，我们目前正在研究对患者更友好且更有效的新配方 我们将充分利用 Drug Delivery Experts LLC（现为 Pace Labs）的优势。 聚乳酸乙醇酸 (PLGA) 无菌注射原位凝胶制剂的配制经验 制造专业知识来完成该项目的 2 个主要目标。 目标 1：完成我们的扩展配方开发并扩大批量生产 释放 PNA5 的原位凝胶注射制剂。 目标 2. 完成缓释注射制剂的体内 PK 研究并与 PNA5 的标准盐水制剂。 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/PK 在我们的 VCID 动物模型中研究 PNA5-PLGA 制剂，以建立认知保护和抗 PNA5-PLGA 的炎症作用并开始正式的毒理学 IND 支持研究。