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

基本信息

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
项目类别：
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

项目摘要

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) 影响美国约 1800 万男性，估计影响 3.22 亿男性到 2025 年将在全球范围内出现。 ED 会对生活质量和福祉产生深远的负面影响，并且通常会与焦虑和抑郁相关的 ED 也带来了巨大的经济负担，价值超过 40 亿美元。 2017 年在美国 ED 是影响微血管系统和紧张的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、糖尿病等，以及常见的慢性疾病前列腺癌治疗的副作用目前可用的 ED 治疗充其量是中等有效的。高停药率，并且只解决症状，而不解决根本原因。对于 ED 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 是一种高度保守的趋化因子，可调节内源性。全身许多组织使用的修复途径，例如心脏、大脑、肌肉和脉管系统。 SDF-1 信号传导通常在损伤后上调，导致干细胞迁移至 SDF-1 结合。其驻留组织上的受体 CXCR4，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。这种 SDF-1 阴茎注射改善了 ED 大鼠模型的勃起功能。改善与主要骨盆神经节（MPG）神经元的增加、阴茎纤维化的减少、阴茎组织中生长因子的表达增加，SDF-1 阴茎注射被证明可以上调。 Evincis 中干细胞相关基因的表达也证明了这一点。阴茎组织中基于 mRNA 的靶向基因表达的可行性事实上，mRNA 技术正在开发中。在此一期项目中，Evincis 将进行体外和体内试验。剂量、功效和安全性研究以支持进一步的临床研究。以下具体目标： 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；3) 执行功效和癌症安全性；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。测试其他疾病状态，研究不同的核酸载体，进行药代动力学和毒理学研究，并启动支持 IND 申请和启动 I 期临床所需的 GMP 设置 Evincis 将寻求作为生物制剂的批准，从而获得产品 J 代码和独立的报销。如果办公室内手术成功，EVI-200 将成为第一种专门用于治疗该病的疗法。神经、肌肉和血管组织损伤导致 ED 的根本原因，并可能提供该项目还将作为 EVI-200 作为 mRNA 的概念验证。基于再生疗法治疗其他疾病，例如尿失禁。