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: 10584478
• 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/10584478
• 关键词: 1 year old; Acute; Aging; Biological Assay; Bone Density; Bone Formation Stimulation; Bone Resorption; Bone Resorption Inhibition; 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; Genetic; Goals; Hormones; Human; Hypogonadism; Investigation; Knockout Mice; Malignant neoplasm of prostate; Maps; Mediating; Memory; Modeling; Molecular; Monitor; Mus; NOS3 gene; Neurons; Nitric Oxide; Oral; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Ovariectomy; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenocopy; Phosphodiesterase Inhibitors; Population; Positive Lymph Node; Prevention; Production; Prostate Cancer therapy; Protein Isoforms; Pulmonary Hypertension; Rattus; Reporting; Rodent Model; Role; Safety; Site; Structure; Surface; Time; Tracer; Transcript; Translations; Virus; Wild Type Mouse; Withdrawal; Woman; Work; aged; androgen deprivation therapy; bone; bone cell; bone loss; bone mass; cellular targeting; drug action; drug repurposing; efficacy study; enzyme activity; gain of function; genetic signature; inhibitor; knock-down; locus ceruleus structure; loss of function; male; men; mineralization; nerve supply; neural; neurogenesis; older men; osteoblast differentiation; ovarian failure; overexpression; paraventricular nucleus; pharmacologic; phosphoric diester hydrolase; preclinical efficacy; preclinical study; prevent; 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.

四种FDA批准的勃起功能障碍药物（即他达拉非、伐地那非、西地那非和阿伐那非）的安全性和有效性记录是基于其强效抑制细胞酶磷酸二酯酶5A（PDE 5A）的能力。PDE 5A水解环磷酸鸟苷（cGMP），因此PDE 5A抑制剂刺激一氧化氮-cGMP-蛋白激酶G（PKG）途径。在1991年，我们第一次证明了一氧化氮调节破骨细胞，骨吸收细胞（PMID：1849281）。此后，多项研究已经确立了调节该途径对骨重塑的两个组分-破骨细胞的骨吸收和成骨细胞的骨形成的强大作用。在老年男性、糖尿病男性和接受雄激素剥夺治疗的前列腺癌男性中，勃起功能障碍和骨质疏松症同时发生，我们试图研究他达拉非和伐地那非对骨的作用。总体假设是，PDE 5A抑制剂可以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，这在雌性小鼠中尤为重要（Kim et al，PNAS，In press）。尽管净骨增加，药物的合成代谢作用被一个独特的交感神经中继签名拮抗，起源于蓝斑，中缝苍白和下丘脑室旁核的中央PDE 5A阳性神经元。注意到大多数骨质疏松症药物是抗吸收或合成代谢，任何双重作用的药物将 具有独特的价值，特别是口服使用。因此，为了重新利用PDE 5A抑制剂治疗骨质疏松症，我们目前的目标是准确了解药物如何作用于骨骼，并评估骨丢失模型的临床前疗效。在具体目标1中，使用整体和细胞选择性敲除小鼠，我们将确定药物是否抑制PDE 5A激活骨中的NO-cGMP-PKG 2通路，如果是，哪个细胞是主要靶点。在具体目标2中，我们将通过RNAscope在单个转录物水平上全面绘制PDE 5A在脑中的分布，并通过AAV介导的Pde 5a过表达或敲低来询问PDE 5A阳性节点。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岁老龄小鼠中引发骨增加的能力;在大鼠和小鼠中预防性腺功能减退性骨丢失的能力;以及在大鼠中恢复卵巢切除术后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的临床试验提供坚实的基础，以重新利用PDE 5A抑制剂预防和治疗骨质疏松症。