Pharmacological Method to Accelerate Bone Fracture Healing

加速骨折愈合的药理学方法

• 批准号: 7998359
• 负责人: J Patrick O'Connor
• 金额: $ 22.88万
• 依托单位: ACCELALOX, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-05 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998359
• 关键词: Adult; Adverse effects; American; Animal Model; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Asthma; Breeding; Canis familiaris; Caring; Child; Clinic; Clinical; Clinical Trials; Development; Diabetes Mellitus; Elderly; Fracture; Fracture Healing; Growth Factor; Half-Life; Hand; Healed; Health Care Costs; Hospitals; Hour; Human; Impaired wound healing; Impairment; Incidence; Injury; Lead; Leg; Legal patent; Length; Licensing; Lipoxygenase Inhibitors; Marketing; Measures; Medical; Methods; Modeling; Muscle; Muscular Atrophy; Nursing Homes; Oral Administration; Orthopedics; Osteoporosis; Osteotomy; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physicians; Positioning Attribute; Process; Property; Quality of life; Radial; Rattus; Rehabilitation therapy; Research; Research Design; Rodent; Small Business Innovation Research Grant; Speed; Testing; Therapeutic; Time; Work; Workplace; arm; base; bone; bone healing; bone morphogenetic protein 7; bone strength; clinically relevant; cost; diabetic patient; disability; economic impact; effective therapy; gastrointestinal system; healing; improved; innovation; preclinical study; public health relevance; recombinant human bone morphogenetic protein-2; small molecule; tibia; wasting

DESCRIPTION (provided by applicant): Bone fractures are common traumatic injuries that often cause temporary disability. In healthy children and adults, fractures normally heal without sequelae, though the temporary disability can lead to muscle atrophy, rehabilitation, and lost time from the work place. Advancing age and other co-morbid conditions, such as diabetes, can greatly increase fracture healing times and reduce overall rates for successful healing. In addition, severe muscle atrophy and prolonged stays at hospitals and rehabilitation or nursing homes are especially common in elderly and diabetic patients. A 25% reduction in healing time would reduce complications and enable people to return to their normal routines much sooner, while dramatically reducing costs associated with healing. Thus a therapy that would accelerate the normal healing process would be of significant benefit to many of the 10 million Americans who suffer a fracture each year. Presently, no such therapy exists. We previously demonstrated that loss or inhibition of COX-2 severely impairs fracture healing. Our tests to understand the mechanism of this impairment led us to test the effects of 5-lipoxygenase (5-LO) inhibitors on the rate of fracture healing. This was based on the idea that when COX-2 is inhibited, arachidonic acid is shunted into the 5-LO pathway and the resulting metabolites slow fracture healing, as detailed in the Background section of this proposal. Following this idea, we have identified a 5-LO inhibitor (A-79175) that reduces the time for fracture healing in rats by 25%, reduced non-unions to 0% from 33% at the experimental endpoint, and increased measures of healed bone strength by 50-90% compared to untreated controls. We have developed a use patent estate for this compound and 5-LO inhibitors in general for bone healing. The composition of matter patent on this compound has lapsed so we can use this compound without having to obtain a license. This compound is a small molecule and is orally available. A-79175 has already successfully passed Phase I human clinical trials for asthma. The half life and other drug-like properties of this molecule, including potency, are well suited for the indication of treating fractures. The aim of this proposal is to demonstrate that A-79175 will accelerate and enhance fracture healing in a higher animal model. A positive finding in this animal model will support the use of 5-LO inhibitors as a therapeutic strategy for fracture care, position A-79175 for an IND application for proof of concept testing in humans, and move our company toward further successful development of the first drug to enhance the rate of bone healing. Increasing the rate of healing could have a large impact on those with factures by improving patient quality of life, reducing recuperation time, muscle wasting, rehabilitation time, incidence of complications, overall health care costs, and more. PUBLIC HEALTH RELEVANCE: Project Narrative We have identified an orally delivered drug that accelerates and enhances fracture healing in small animal models. Bone fractures are common traumatic injuries. Complications associated with fractures include delayed healing or failed healing (non-unions) and attending disability and muscle atrophy. Common pathological conditions such as osteoporosis and diabetes increase the incidence of fractures or significantly impair healing. Presently, there is no cost-effective therapy to prospectively treat fractures to reduce time to healing or reduce the incidence of delayed healing or non-union. This project will test our newly identified therapy in a clinically relevant animal model to confirm our previous findings and justify testing in humans.

描述（由申请人提供）：骨折是常见的外伤，通常会导致暂时残疾。对于健康的儿童和成人，骨折通常会愈合，不会留下后遗症，但暂时的残疾可能会导致肌肉萎缩、康复和失去工作时间。高龄和其他合并症（例如糖尿病）会大大增加骨折愈合时间并降低总体成功愈合率。此外，严重的肌肉萎缩和长时间住院、康复或疗养院在老年和糖尿病患者中尤其常见。治愈时间缩短 25% 将减少并发症，使人们能够更快地恢复正常生活，同时大大降低与治愈相关的成本。因此，一种能够加速正常愈合过程的疗法将为每年遭受骨折的 1000 万美国人中的许多人带来重大益处。目前，尚不存在这样的疗法。 我们之前证明 COX-2 的缺失或抑制会严重损害骨折愈合。为了了解这种损伤的机制，我们进行了测试，测试了 5-脂氧合酶 (5-LO) 抑制剂对骨折愈合速度的影响。这是基于这样的想法：当 COX-2 受到抑制时，花生四烯酸被分流到 5-LO 途径中，产生的代谢物会减缓骨折愈合，如本提案背景部分所述。遵循这一想法，我们发现了一种 5-LO 抑制剂 (A-79175)，可将大鼠骨折愈合时间缩短 25%，在实验终点将不愈合率从 33% 降至 0%，并增加愈合测量值与未经治疗的对照组相比，骨强度增加 50-90%。我们已经开发了该化合物和 5-LO 抑制剂用于骨愈合的用途专利。该化合物的物质组合物专利已经失效，因此我们可以使用该化合物而无需获得许可。该化合物是一种小分子，可口服。 A-79175已成功通过哮喘一期人体临床试验。该分子的半衰期和其他类似药物的特性（包括效力）非常适合治疗骨折的适应症。 该提案的目的是证明 A-79175 将在高等动物模型中加速和增强骨折愈合。该动物模型中的积极发现将支持使用 5-LO 抑制剂作为骨折护理的治疗策略，将 A-79175 定位为 IND 应用以进行人体概念验证测试，并推动我们公司进一步成功开发首先是增强骨愈合速度的药物。提高愈合率可以改善患者的生活质量、减少康复时间、肌肉萎缩、康复时间、并发症的发生率、总体医疗保健费用等，从而对骨折患者产生重大影响。 公共卫生相关性：项目叙述我们已经确定了一种口服药物，可以在小动物模型中加速和增强骨折愈合。骨折是常见的外伤。与骨折相关的并发症包括愈合延迟或愈合失败（不愈合）以及主治残疾和肌肉萎缩。骨质疏松症和糖尿病等常见病理状况会增加骨折的发生率或严重损害愈合。目前，尚无经济有效的疗法可以前瞻性地治疗骨折以缩短愈合时间或降低延迟愈合或不愈合的发生率。该项目将在临床相关的动物模型中测试我们新发现的疗法，以证实我们之前的发现并证明在人体中进行测试的合理性。