SDF-1 mRNA gene therapy for restoration of erectile function

摘要 勃起功能障碍(ED)在美国影响着大约1800万男性，据估计影响3.22亿男性 到2025年在全球范围内。勃起功能障碍会对生活质量和幸福感产生深远的负面影响，而且经常 与焦虑和抑郁有关。对外债务也是一个重大的经济负担，超过40亿美元 2017年在美国度过的ED是影响微血管和神经的疾病的常见后果 组织，包括常见的慢性疾病，如高血压、血脂异常和糖尿病，以及频繁的 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，有 戒毒率高，只针对症状，而不是根本原因。为了满足这种需求 对于ED的新治疗方法，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)基因。SDF-1是一种高度保守的趋化因子，调节内源性 修复途径全身许多组织，如心脏、脑、肌肉和血管系统使用的修复途径。 SDF-1信号通常在损伤后上调，导致干细胞迁移到损伤部位。SDF-1绑定到 其受体CXCR4在包括神经、肌肉和血管在内的常驻组织上，诱导血管生成， 神经发生，抗凋亡途径，以及上调生长因子的表达。埃文吉斯已经 结果表明，注射SDF-1可改善勃起功能障碍大鼠的勃起功能。这 改善与主要骨盆神经节(MPG)神经元增加，阴茎纤维化减轻， 以及阴茎组织中生长因子的表达增加。研究表明，注射SDF-1阴茎可上调 干细胞相关基因在MPG和勃起组织中的表达。Evincis还展示了 阴茎组织靶向基因表达的可行性研究。事实上，信使核糖核酸技术正在 目前几种新冠肺炎疫苗都在使用。在这个第一阶段的项目中，Evincis将在体外和体内进行 剂量、有效性和安全性研究，以支持进一步的临床研究。这将通过 具体目标如下：1)体外筛选表达效率和细胞毒性的基因工程候选基因； 2)确定EVI-200的剂量、表达持续时间和体内安全性；以及3)执行有效性和癌症安全性 活体研究。这些研究将支持进一步的第二阶段工作，在该阶段，Evincis将扩大临床前 检测其他疾病状态，调查不同的核酸携带者，执行药代动力学和 毒理学研究，并启动支持IND应用程序和启动I期临床所需的GMP设置 审判。Evincis将寻求批准作为生物，导致产品J代码和独立的报销 办公室内程序。如果成功，EVI-200将成为第一个专门设计用于治疗 由于神经、肌肉和血管组织的损伤而导致的ED的潜在原因，并可能提供 治愈数以百万计的人。该项目还将作为EVI-200作为信使核糖核酸的概念验证。 对于其他情况，如尿失禁，以再生疗法为基础。

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.