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）：骨骼骨折是常见造成暂时残疾的常见创伤性伤害。在健康的儿童和成人中，骨折通常在没有后遗症的情况下愈合，尽管暂时的残疾会导致肌肉萎缩，康复和工作场所的时间浪费。促进年龄和其他合并症（例如糖尿病）可以大大增加骨折的愈合时间，并降低成功愈合的总体率。此外，在老年人和糖尿病患者中，严重的肌肉萎缩和长时间住宿，康复或疗养院尤为常见。康复时间减少25％将减少并发症，并使人们能够早日恢复正常的例程，同时大大降低与康复相关的成本。因此，一种可以加速正常愈合过程的疗法将对每年遭受骨折的1000万美国人中的许多人带来重大好处。目前，没有这种疗法。 我们先前证明了COX-2的损失或抑制严重损害了断裂的愈合。我们的测试以了解这种损伤的机制，使我们测试了5-脂氧合酶（5-LO）抑制剂对骨折愈合率的影响。这是基于这样的想法：当COX-2被抑制时，蛛网膜酸被分成5-LO途径，所得代谢产物慢性断裂愈合，如本提案的背景部分所述。遵循这个想法，我们已经确定了一个5-LO抑制剂（A-79175），该抑制剂将大鼠断裂愈合的时间降低了25％，在实验终点下，非工会从33％降低至0％，与未经处理的对照相比，在实验端点的骨骼愈合时间增加了50-90％。我们已经开发了该化合物和5-LO抑制剂的使用专利遗产用于骨骼愈合。该化合物上物质专利的构成已经消失，因此我们可以使用该化合物而无需获得许可。该化合物是一个小分子，可以口服。 A-79175已经成功地通过了I期哮喘的I期临床试验。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指示。 该提案的目的是证明A-79175将在较高的动物模型中加速并增强骨折愈合。该动物模型中的一个积极发现将支持使用5-LO抑制剂作为断裂护理的治疗策略，将A-79175定位为IND应用于人类的概念证明，并使我们的公司进一步成功开发了第一种药物以提高骨骼愈合的速度。通过提高患者生活质量，减少疗养时间，肌肉浪费，康复时间，并发症的发生率，整体医疗保健费用等，可以提高康复率对患有尸体的人会产生很大的影响。 公共卫生相关性：我们已经确定了一种口服交付的药物，可加速和增强小动物模型中的骨折愈合。骨折是常见的创伤性伤害。与骨折有关的并发症包括延迟愈合或愈合失败（非工会）以及参加残疾和肌肉萎缩。骨质疏松和糖尿病等常见病理状况会增加骨折的发生率或显着损害愈合。目前，没有具有成本效益的治疗方法可以预期治疗骨折以减少愈合时间或减少延迟愈合或非工会的发生率。该项目将在临床相关的动物模型中测试我们新鉴定的疗法，以确认我们以前的发现并证明在人类中的测试是合理的。