SDF-1 mRNA gene therapy for restoration of erectile function

用于恢复勃起功能的 SDF-1 mRNA 基因治疗

• 批准号: 10325466
• 负责人: Nikolai Anton Sopko
• 金额: $ 31.49万
• 依托单位: EVINCIS BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325466
• 关键词: Address; Adipose tissue; Adrenergic alpha-Antagonists; Affect; American; Anxiety; Apoptotic; Binding; Biological; Blood Platelets; Blood Vessels; Brain; COVID-19 vaccine; CXCR4 Receptors; Cardiovascular Agents; Chronic Disease; Cialis; Clinic; Clinical Research; Code; Data; Devices; Diabetes Mellitus; Disease; Dose; Drug Interactions; Drug Kinetics; Dyslipidemias; Economic Burden; Engineering; Erectile dysfunction; Fibrosis; Ganglia; Gene Expression; Genes; Growth Factor; Heart; Heart Diseases; Hypertension; In Vitro; Individual; Injection of therapeutic agent; Injections; Injury; Insurance; Investigational Drugs; Investigational New Drug Application; Maintenance; Malignant Neoplasms; Mental Depression; Messenger RNA; Modality; Modeling; Muscle; Nerve; Nerve Tissue; Neurons; Nitrates; Nucleic Acids; Oral; Pathway interactions; Patients; Pelvis; Penile Prosthesis; Performance; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Plasma; Porifera; Preclinical Testing; Procedures; Prostate Cancer therapy; Proteins; Public Health; Quality of life; Randomized Controlled Trials; Rattus; Safety; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Standardization; Stromal Cell-Derived Factor 1; Symptoms; Technology; Tissues; Toxicology; Translating; Treatment Protocols; Urinary Incontinence; Vacuum; Vasodilator Agents; Viagra; Work; angiogenesis; base; chemokine; clinical infrastructure; cytotoxicity; design; dosage; drug distribution; efficacy study; gene therapy; healing; improved; in vivo; inhibitor/antagonist; injured; men; minimally invasive; nerve injury; neurogenesis; novel; penis; phosphoric diester hydrolase; regenerative; regenerative therapy; repaired; restoration; safety study; side effect; stem cell migration; stem cells; uptake; vardenafil

Abstract Erectile dysfunction (ED) affects about 18 million men in the U.S. and is estimated to affect 322 million men worldwide by 2025. ED can have a profound negative impact on quality of life and well-being and is often associated with anxiety and depression. ED also represents a significant economic burden, with over $4 billion spent in 2017 in the U.S. ED is a common consequence of diseases that affect the microvasculature and nervous tissue, including common chronic diseases such as hypertension, dyslipidemia, and diabetes, and a frequent side effect of prostate cancer treatment. Currently available ED treatments are moderately effective at best, have high discontinuation rates, and address only the symptoms, not the underlying causes. To address the need for novel treatments for ED, Evincis Bio is developing a regenerative gene therapy based on stromal cell‐derived factor‐1 (SDF-1) mRNA. SDF-1 is a highly conserved chemokine that regulates an endogenous repair pathway used by many tissues throughout the body, such as the heart, brain, muscle, and vasculature. Often upregulated following injury, SDF-1 signaling leads to stem cell migration to the injury site. SDF-1 binds to its receptor CXCR4 on resident tissues, including nerves, muscle, and vasculature, inducing angiogenesis, neurogenesis, anti-apoptotic pathways, and upregulating the expression of growth factors. Evincis has demonstrated that SDF-1 penile injections improve erectile function in a rat model of ED. This improvement was associated with increased major pelvic ganglion (MPG) neurons, decreased penile fibrosis, and increased growth factor expression in penile tissues. SDF-1 penile injections were shown to upregulate the expression of stem cell-associated genes in the MPG and erectile tissue. Evincis has also demonstrated the feasibility of targeted mRNA-based gene expression in penile tissues. In fact, mRNA technology is being utilized by several current COVID-19 vaccines. In this Phase I project, Evincis will conduct in vitro and in vivo dosing, efficacy, and safety studies to support further clinical research. This will be accomplished through the following specific aims: 1) Screen engineered mRNA candidates in vitro for expression efficiency and cytotoxicity; 2) Determine EVI-200 dosage, expression duration, and safety in vivo; and 3) Perform efficacy and cancer safety studies in vivo. These studies will support further Phase II work, in which Evincis will expand the preclinical testing to additional disease states, investigate different nucleic acid carriers, perform pharmacokinetic and toxicology studies, and initiate the GMP setup necessary to support an IND application and start a Phase I clinical trial. Evincis will pursue approval as a biologic, resulting in a product J-code and stand-alone reimbursement for the in-office procedure. If successful, EVI-200 will be the first therapy specifically designed to treat the underlying causes of ED due to injury of nerve, muscle, and vascular tissue, and potentially provide a cure for millions of individuals. This project will also serve as a proof-of-concept for EVI-200 as an mRNA- based regenerative therapy for other conditions, such as urinary incontinence.

抽象的 勃起功能障碍（ED）在美国影响约1800万人，估计会影响3.22亿人 到2025年，全世界。 与焦虑和抑郁有关。埃德还代表了一个巨大的经济伯恩，超过40亿美元 2017年在美国的支出是影响微脉管系统和紧张的疾病的普遍结果 组织，包括常见的慢性疾病，例如高血压，血脂异常和糖尿病，以及频率 前列腺癌治疗的副作用。目前可用的ED治疗充其量是中等效率的， 高度停产率，仅解决症状，而不是基本原因。解决需求 对于ED的新型治疗，Evincis Bio正在基于基质的再生基因疗法开发 细胞来源的因子1（SDF-1）mRNA。 SDF-1是一种高度保守的趋化因子，可调节内源性 整个身体的许多组织使用的修复途径，例如心脏，大脑，肌肉和脉管系统。 受伤后通常会上调，SDF-1信号传导导致干细胞迁移到损伤部位。 SDF-1与 它的受体CXCR4在居民组织上，包括神经，肌肉和脉管系统，诱导血管生成， 神经发生，抗凋亡途径和上调生长因子的表达。 Evincis拥有 证明SDF-1阴茎注射改善了ED大鼠模型中的勃起功能。这 改善与增加的骨盆神经节（MPG）神经元增加有关，改善了阴茎纤维化， 并增加了阴茎组织中生长因子的表达。 SDF-1阴茎注射显示可更新 MPG和勃起组织中与干细胞相关基因的表达。 Evincis也证明了 靶向mRNA基因表达在阴茎组织中的可行性。实际上，mRNA技术正在 由几种当前的Covid-19疫苗使用。在这个阶段的项目中，Evincis将在体外和体内进行体外进行 剂量，有效性和安全研究以支持进一步的临床研究。这将通过 以下特定目的：1）筛选在体外进行了筛选的候选mRNA，以表达效率和细胞毒性； 2）确定体内EVI-200剂量，表达持续时间和安全性； 3）执行效率和癌症安全 体内研究。这些研究将支持进一步的第二阶段工作，其中Evincis将扩大临床前 对其他疾病状态进行测试，研究不同的核酸载体，执行药代动力学和 毒理学研究，并启动为支持IND应用所需的GMP设置，并开始I期临床 审判。 Evincis将作为生物学寻求批准，从而导致产品J代码和独立报销 办公室程序。如果成功的话，EVI-200将是专门设计用于治疗的疗法 由于神经，肌肉和血管组织的损伤，ED的根本原因，并可能提供 治愈数百万个人。该项目还将作为EVI-200作为mRNA-的概念概念证明 - 基于其他疾病（例如尿失禁）的再生疗法。