Localized SDF-1 mRNA nanoparticle delivery for treating erectile dysfunction.

局部 SDF-1 mRNA 纳米颗粒递送用于治疗勃起功能障碍。

• 批准号: 10608145
• 负责人: Johanna Lucy Hannan
• 金额: $ 16.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608145
• 关键词: Affect; Age; Architecture; Biological Products; Cell Nucleus; Cells; Characteristics; Chemicals; Chronic; Cialis; Clinical; Clinical Research; Custom; Data; Defect; Diabetes Mellitus; Disease; Dose; Drug Interactions; Economics; Endocrine system; Engineering; Environment; Erectile dysfunction; Excision; Exhibits; Fibrosis; Formulation; Frequencies; Functional disorder; Ganglia; Genes; Goals; Growth Factor; Half-Life; Health; Histology; Human; Hypertension; In Vitro; Individual; Injections; Injury; Insertional Mutagenesis; Kinetics; Lead; Malignant neoplasm of prostate; Measures; Messenger RNA; Modality; Modeling; Muscle; Natural regeneration; Nerve; Nervous System; Neurons; Oral; Pathology; Pathway interactions; Patients; Pelvis; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Polymers; Population; Prostate Cancer therapy; Prostatectomy; Proteins; Quality of life; Radical Prostatectomy; Rattus; Recombinants; Regimen; Reporter; Risk; Rodent; Safety; Smooth Muscle; Stromal Cell-Derived Factor 1; Study models; System; Therapeutic; Time; Tissues; Transfection; Treatment Efficacy; Up-Regulation; Urology; Variant; Vascular System; Viagra; clinical development; clinically relevant; curative treatments; delivery vehicle; design; improved; in vivo; inhibitor; injured; interest; lead candidate; mRNA Expression; mRNA delivery; male; men; multidisciplinary; nanoparticle; nanoparticle delivery; nanopolymer; neurovascular; neurovascular injury; novel; nucleic acid delivery; penis; phosphoric diester hydrolase; plasmid DNA; pre-clinical; preclinical study; prevent; prostate cancer model; repaired; response; safety study; side effect; standard of care; stem cells; symptom management; symptomatic improvement

PROJECT SUMMARY About 18 million men in the U.S. are affected by erectile dysfunction (ED), and it is estimated to affect 322 million men worldwide by 2025. ED is caused by various conditions that perturb vascular, nervous and/or hormonal systems, imposing profound negative impacts on quality of life and well-being of affected males. Advent of oral formulations of phosphodiesterase type 5 inhibitors (e.g., Viagra®) has provided a breakthrough in managing ED to a certain degree but are frequently ineffective due to underlying neurovascular dysfunction, and often accompanies systemic side effects and undesired drug-drug interactions. To this end, a therapeutic modality that can intervene the natural histology of the disease among a broader affected population is sorely needed. We have recently discovered that human recombinant stromal cell-derived factor-1 (SDF-1) promotes regeneration of penile vasculatures, nerves and muscles to restore erectile function in a rat model of ED. The improvement was associated with increases in major pelvic ganglion neurons and growth factor expression, upregulation of stem-cell associated genes and decrease in penile fibrosis. Importantly, SDF-1 targets a broad array of repair mechanisms by acting directly on resident tissues and activating stem-cell associated repair pathways to enhance the integrity of tissue architecture and functional response. However, protein-based therapy requires multiple and frequent doses to meet the required therapeutic window, leading to economic and compliance issues. This is of particular concern for SDF-1 due to its very short half-live, measured in minutes. We thus propose here to develop mRNA-based SDF-1 therapy, with a particular focus on designing nanoparticle-based platforms providing safety and efficient mRNA delivery to penile cells, for sustainable ED treatment. Our interest lies in nanoparticles based on environmentally-sensitive cationic polymers that gradually degrade in physiological environments to facilitate mRNA release, ideally in intracellular milieu, and removal of carrier materials from body. Encouragingly, our pilot data demonstrates that at least four nanoparticles based on our custom-synthesized polymers provide significantly enhanced reporter mRNA expression in rodent penile tissues in vivo compared to a gold-standard polymeric delivery system. We note that chemical variations of these polymers can further improve mRNA delivery characteristics, such as broader tissue coverage and/or enhanced transfection efficiency. To this end, we will synthesize a panel of chemically- distinct environmentally-sensitive polymers and extensive screen in vitro and in vivo to determine lead candidates that provide highly efficiently and safe penile mRNA expression. The lead candidates will then be used to package and deliver optimized SDF-1 mRNA into the injured penile tissues of a rat model of ED to establish clinical relevance. Successful execution of the proposed studies would pave the way for clinical development of novel mRNA-based therapy for treating patients with ED, particularly those poorly responsive to current standard-of-care treatments.

项目摘要 美国约有1800万人受到勃起功能障碍（ED）的影响，据估计会影响 到2025年，全球3.22亿男性是由扰动血管，紧张和/或的各种情况引起的 荷尔蒙系统对受影响男性的生活质量和福祉产生了深远的负面影响。 磷酸二酯酶5型抑制剂（例如伟哥®）的口服配方的出现提供了突破 在某种程度上管理ED，但由于潜在的神经血管功能障碍而经常无效， 并且通常涉及系统性副作用和不希望的药物相互作用。为此，一种治疗性 可以干预疾病的自然组织学在受影响的广泛的人群中的模式非常 需要。我们最近发现，人重组基质细胞衍生的因子1（SDF-1）促进 在ED大鼠模型中，阴茎血管，神经和肌肉的再生恢复勃起功能。 改善与主要的骨盆神经元神经元和生长因子表达的增加有关， 干细胞相关基因的上调和阴茎纤维化的减少。重要的是，SDF-1针对广泛 通过直接作用于居民组织和激活干细胞相关修复来进行修复机制阵列 增强组织结构和功能响应的完整性的途径。但是，基于蛋白质 治疗需要多种剂量才能满足所需的治疗窗口，从而导致经济 和合规性问题。这是SDF-1由于其非常短的半寿命而尤其关注的，以此测量 分钟。因此，我们在这里建议开发基于mRNA的SDF-1疗法，特别着眼于设计 基于纳米颗粒的平台，可提供安全性和有效的mRNA向阴茎细胞传递，以实现可持续性ED 治疗。我们的兴趣在于基于对环境敏感的阳离子聚合物的纳米颗粒 在物理环境中逐渐降解以促进mRNA释放，理想情况下在细胞内环境中，并且 从人体中去除载体材料。令人鼓舞的是，我们的飞行员数据表明​​至少四个 基于我们自定义合成的聚合物的纳米颗粒提供了明显增强的记者mRNA 与金色标准的聚合物输送系统相比，体内啮齿动物阴茎时机的表达。我们注意 这些聚合物的化学变化可以进一步改善mRNA递送特性，例如更广泛 组织覆盖范围和/或增强的转化效率。为此，我们将合成一组化学的面板 不同环境敏感的聚合物和体外和体内广泛的屏幕以确定铅 提供高效且安全的阴茎mRNA表达的候选者。然后，候选人将是 用于将优化的SDF-1 mRNA包装并输送到ED大鼠模型的受伤的阴茎时间到 建立临床相关性。成功执行拟议的研究将为临床铺平道路 开发基于MRNA的新型治疗ED患者，尤其是那些反应良好的疗法 到当前的护理标准治疗。