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.

摘要 勃起功能障碍（艾德）影响美国约1800万男性，估计影响3.22亿男性 到2025年全球艾德可对生活质量和健康产生深远的负面影响， 与焦虑和抑郁有关。艾德也是一个巨大的经济负担， 艾德是影响微血管和神经系统疾病的常见后果。 组织，包括常见的慢性疾病，如高血压，血脂异常和糖尿病，以及常见的 前列腺癌治疗副作用目前可用的艾德治疗充其量是中等有效的， 高停药率，并且只解决症状，而不是根本原因。为了满足 对于艾德的新疗法，Evincis Bio正在开发一种基于基质的再生基因疗法。 细胞衍生因子-1（SDF-1）mRNA。SDF-1是一种高度保守的趋化因子，调节内源性 修复途径，用于全身许多组织，如心脏、大脑、肌肉和脉管系统。 通常在损伤后上调，SDF-1信号传导导致干细胞迁移到损伤部位。SDF-1与 其受体CXCR 4在包括神经、肌肉和脉管系统的驻留组织上，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已经 证明SDF-1阴茎注射改善ED大鼠模型的勃起功能。 改善与主要盆神经节（MPG）神经元增加，阴茎纤维化减少， 并增加阴茎组织中生长因子的表达。SDF-1阴茎注射显示上调了 MPG和勃起组织中干细胞相关基因的表达。Evincis还展示了 阴茎组织中靶向mRNA基因表达的可行性。事实上，mRNA技术 目前的几种COVID-19疫苗都利用了这一点。在这个I期项目中，Evincis将在体外和体内进行 剂量、疗效和安全性研究，以支持进一步的临床研究。这将通过以下方式实现： 具体目的如下：1）体外筛选工程化mRNA候选物的表达效率和细胞毒性; 2)确定EVI-200剂量、表达持续时间和体内安全性;以及3）进行功效和癌症安全性研究。 体内研究。这些研究将支持进一步的II期工作，其中Evincis将扩大临床前研究。 检测其他疾病状态，研究不同的核酸携带者，进行药代动力学和 毒理学研究，并启动支持IND申请所需的GMP设置，并开始I期临床试验 审判Evincis将寻求作为生物制剂的批准，从而获得产品J代码和独立报销， 办公室内的程序。如果成功，EVI-200将是第一个专门设计用于治疗 由于神经、肌肉和血管组织损伤而导致艾德的根本原因，并可能提供一种治疗方法 治愈数百万人。该项目还将作为EVI-200作为mRNA的概念验证- 基于再生治疗的其他条件，如尿失禁。