Proof-of-Concept and Mechanistic Studies to Repurpose Erectile Dysfunction Drugs for Elderly Females

重新利用老年女性勃起功能障碍药物的概念验证和机制研究

• 批准号: 10400135
• 负责人: Se-min Kim
• 金额: $ 69.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400135
• 关键词: 1 year old; Acute; Aging; Androgens; Biological Assay; Bone Density; Bone Resorption; Bone remodeling; Brain; Brain region; Cells; Clinical Trials; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus; Elderly; Elderly man; Elderly woman; Enzymes; Erectile dysfunction; Excision; FDA approved; Female; Foundations; Future; Genes; Genetic; Goals; Hormones; Human; Hypogonadism; Investigation; Knockout Mice; Malignant neoplasm of prostate; Maps; Mediating; Minerals; Modeling; Molecular; Monitor; Mus; NOS3 gene; Neurons; Nitric Oxide; Oral; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Ovariectomy; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenocopy; Phosphodiesterase Inhibitors; Population; Positive Lymph Node; Prevention; Production; Prostate Cancer therapy; Protein Isoforms; Pulmonary Hypertension; Rattus; Reporting; Rodent Model; Role; Safety; Site; Surface; Time; Tracer; Transcript; Translations; Virus; Wild Type Mouse; Withdrawal; Woman; Work; aged; androgen deprivation therapy; base; bone; bone cell; bone loss; bone mass; cellular targeting; deprivation; drug action; drug repurposing; efficacy study; enzyme activity; gain of function; inhibitor; knock-down; locus ceruleus structure; male; men; nerve supply; neurogenesis; older men; osteoblast differentiation; ovarian failure; overexpression; paraventricular nucleus; phosphoric diester hydrolase; preclinical efficacy; preclinical study; prevent; relating to nervous system; sildenafil; skeletal; small molecule inhibitor; tadalafil; vardenafil

The record of safety and efficacy of the four FDA–approved drugs for erectile dysfunction, namely tadalafil, vardenafil, sildenafil and avanafil, is predicated on their ability to potently inhibit the cellular enzyme, phosphodiesterase 5A (PDE5A). PDE5A hydrolyzes cyclic guanosine monophosphate (cGMP), so that PDE5A inhibitors stimulate the nitric oxide–cGMP–protein kinase G (PKG) pathway. In 1991, we documented for the first time that nitric oxide regulates the osteoclast, the cell that resorbs bone (PMID: 1849281). Multiple studies have since established robust effects of modulating this pathway on both components of bone remodeling – bone resorption by osteoclasts and bone formation by osteoblasts. Prompted by observations that erectile dysfunction and osteoporosis track together in older men, in men with diabetes, and in men receiving androgen–deprivation therapy for prostate cancer, we sought to investigate the action of tadalafil and vardenafil on bone. The overarching hypothesis was that PDE5A inhibitors could be repurposed for the co–therapy of erectile dysfunction and osteoporosis in men and, even perhaps, solely for osteoporosis in women. We found in mouse studies that tadalafil and vardenafil increased bone mass, importantly in female mice, by stimulating bone formation and inhibiting bone resorption (Kim et al, PNAS, In press). Despite net bone gain, the anabolic action of the drugs was antagonized by a unique sympathetic relay signature originating from central PDE5A–positive neurons in the locus coeruleus, raphe pallidus and hypothalamic paraventricular nucleus. Noting that most osteoporosis drugs are either anti–resorptive or anabolic, any dual–acting agent will have unique value particularly with oral use. Therefore, towards the potential for repurposing PDE5A inhibitors for osteoporosis, our current goal is to understand precisely how the drugs work on bone and to evaluate preclinical efficacy in models of bone loss. In Specific Aim 1, using global and cell–selective knock out mice, we will determine whether the drugs inhibit PDE5A to activate the NO–cGMP–PKG2 pathway in bone, and if so, which cell is the primary target. In Specific Aim 2, we will comprehensively map the distribution of PDE5A in brain at the single transcript level by RNAscope, and interrogate PDE5A–positive nodes through AAV–mediated Pde5a overexpression or knock down. In Specific Aim 3, we will study the ability of tadalafil, vardenafil, sildenafil and/or avanafil to trigger bone gain in 1–year–old aging mice; to prevent hypogonadal bone loss in rats and mice; and to restore bone that is already lost 28 weeks following ovariectomy in rats. Together, our mechanistic and efficacy studies should provide a firm foundation for future clinical trials towards repurposing PDE5A inhibitors for the prevention and treatment of osteoporosis.

FDA批准的四种治疗勃起功能障碍的药物，即他达拉非、伐地那非、西地那非和伐那非，其安全性和有效性的记录是基于它们有效抑制细胞酶--磷酸二酯酶5A(PDE5A)的能力。PDE5A水解环鸟苷一磷酸(CGMP)，使PDE5A抑制剂刺激一氧化氮-cGMP-蛋白激酶G(PKG)途径。1991年，我们首次证明了一氧化氮调节破骨细胞，破骨细胞是吸收骨的细胞(PMID：1849281)。自那以后，多项研究证实了调节这一途径对骨重建的两个组成部分--破骨细胞的骨吸收和成骨细胞的骨形成--的强大影响。在观察到勃起功能障碍和骨质疏松症在老年男性、糖尿病男性和前列腺癌接受雄激素剥夺治疗的男性中同时存在的情况下，我们试图调查他达拉非和伐地那非对骨骼的作用。最重要的假设是，PDE5A抑制剂可以被重新用于男性勃起功能障碍和骨质疏松症的联合治疗，甚至可能仅用于女性的骨质疏松症。我们在小鼠研究中发现，他达拉非和伐地那非通过刺激骨形成和抑制骨吸收增加骨量，尤其是在雌性小鼠中(Kim等人，PNAS，在出版社)。尽管骨量增加，但药物的合成代谢作用被来自蓝斑、中缝苍白带和下丘脑室旁核的中枢PDE5A阳性神经元的独特交感传递信号所拮抗。请注意，大多数骨质疏松症药物要么是抗吸收药物，要么是合成代谢药物，任何双重作用的药物都会 具有独特的价值，特别是在口服使用时。因此，对于改变PDE5A抑制剂治疗骨质疏松症的可能性，我们目前的目标是准确地了解这些药物对骨的作用方式，并在骨丢失模型中评估临床前的疗效。在特定目标1中，利用全局和细胞选择性基因敲除小鼠，我们将确定这些药物是否抑制PDE5A激活骨骼中的NO-cGMP-PKG2途径，如果是的话，哪个细胞是主要靶点。在具体目标2中，我们将利用RNAScope在单个转录水平上全面定位PDE5A在脑内的分布，并通过AAV介导的Pde5a过表达或敲除来询问PDE5A阳性结节。在具体目标3中，我们将研究他达拉非、伐地那非、西地那非和/或阿伐那非在1岁大的衰老小鼠中引发骨生长的能力；防止大鼠和小鼠性腺功能减退的骨丢失；以及恢复大鼠卵巢切除后28周已经丢失的骨的能力。总之，我们的机制和疗效研究应该为未来重新调整PDE5A抑制剂用于预防和治疗骨质疏松症的临床试验提供坚实的基础。