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 在美国，大约有1800万男性受到勃起功能障碍（艾德）的影响，据估计， 到2025年，全球将有3.22亿男性。艾德是由扰乱血管、神经和/或神经系统的各种病症引起的。 荷尔蒙系统，对受影响男性的生活质量和福祉产生深远的负面影响。 磷酸二酯酶5型抑制剂口服制剂的出现（例如，Viagra®）提供了突破 在一定程度上控制艾德，但由于潜在的神经血管功能障碍而经常无效， 并且经常伴随全身副作用和不希望的药物-药物相互作用。为此，一种治疗 一种可以在更广泛的受影响人群中干预疾病的自然组织学的方式， needed.我们最近发现，人重组基质细胞衍生因子-1（SDF-1）可促进 阴茎血管、神经和肌肉的再生以恢复ED大鼠模型的勃起功能。 改善与主要盆神经节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针对广泛的 通过直接作用于驻留组织并激活干细胞相关修复， 途径，以增强组织结构和功能反应的完整性。然而，基于蛋白质 治疗需要多次和频繁的剂量，以满足所需的治疗窗口，导致经济 和遵守问题。由于SDF-1的半衰期非常短，这一点尤其令人担忧， 分钟因此，我们在这里提出开发基于mRNA的SDF-1治疗，特别关注设计 基于纳米颗粒的平台为阴茎细胞提供安全有效的mRNA递送，用于可持续的艾德 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， 在生理环境中逐渐降解以促进mRNA释放，理想地在细胞内环境中，和 从身体中去除载体材料。令人鼓舞的是，我们的试点数据表明，至少有四个 基于我们定制合成的聚合物的纳米颗粒可显着增强报告mRNA 与金标准聚合物递送系统相比，在啮齿动物阴茎组织中的体内表达。我们注意到 这些聚合物的化学变化可以进一步改善mRNA递送特性，例如更广泛的 组织覆盖和/或增强的转染效率。为此，我们将合成一组化学- 独特的环境敏感聚合物和广泛的体外和体内筛选，以确定铅 提供高效和安全的阴茎mRNA表达的候选物。主要候选人将是 用于将优化的SDF-1 mRNA包装并递送到艾德大鼠模型的受损阴茎组织中， 建立临床相关性。拟议研究的成功执行将为临床研究铺平道路。 开发新的基于mRNA的治疗方法，用于治疗艾德患者，特别是那些反应差的患者 目前的标准治疗方法。