Drug-eluting Stapes Prosthesis for the Prevention of Sensorineural Hearing Loss

药物洗脱镫骨假体预防感音神经性听力损失

• 批准号: 8416900
• 负责人: MICHAEL J. MCKENNA
• 金额: $ 32.85万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416900
• 关键词: Acquired Deafness; Action Potentials; Acute; Adverse effects; Animal Experiments; Animal Model; Animals; Auditory; Auditory Brainstem Responses; Biological Assay; Biomedical Engineering; Bone necrosis; Bone remodeling; Bypass; Cavia; Clinical Trials; Collaborations; Confocal Microscopy; Data; Development; Devices; Disease; Drug Delivery Systems; Drug Formulations; Ensure; Exhibits; Fluorescein; Fluorescence; Fluorescence Microscopy; Goals; Histologic; Human; Implant; Jaw; Kinetics; Knockout Mice; Laboratories; Labyrinth; Lead; Long-Term Effects; Measures; Membrane; Methods; Monitor; Mus; Otologic Surgical Procedures; Otosclerosis; Pathologic; Patients; Performance; Pharmaceutical Preparations; Physiological; Polymers; Prevention; Prosthesis; Research; Risedronate; Safety; Scala Tympani; Secure; Sensorineural Hearing Loss; Stapes; Techniques; Testing; Time; Tissues; Tympanic membrane; Zoledronate; biomaterial compatibility; bisphosphonate; bone; capsule; design; dosage; drug distribution; experience; hearing impairment; improved; inhibitor/antagonist; inner ear diseases; innovation; middle ear; molecular pathology; otoacoustic emission; ototoxicity; prevent; public health relevance; research study; round window; skeletal; technology development; treatment strategy

DESCRIPTION (provided by applicant): Otosclerosis is a disease of the otic capsule that is among the most common causes of acquired hearing loss. During the last fifteen years, our laboratory has focused on elucidating the molecular pathology of otosclerosis with the long-term goal of developing better forms of therapy. These studies have led us to a new and innovative treatment strategy: the inner ear delivery of bisphosphonates via a drug-eluting polymer. We have begun to develop and test a drug formulation for use in humans, and have developed an animal model to test it. Since most patients with otosclerosis receive stapes prosthesis, we will integrate the polymer into the prosthesis for intracochlear delivery. We will also integrate the polymer into a wafer for delivery via the round window membrane. The otic capsule is unique in that it normally exhibits little or no bone remodeling. Otosclerosis is characterized by an abnormal remodeling of the otic capsule. Some bisphosphonate compounds are potent inhibitors of bone remodeling, but potentially serious side effects can occur with systemic administration in humans such as inhibition of all skeletal remodeling and osteonecrosis of the jaw. Intracochlear and intratympanic administration should bypass these systemic problems and ensure that the drugs reach cochlear tissues and the otic capsule in the form and concentration desired. We have identified an animal model, the OPG-/- (knockout) mouse, which exhibits foci of active remodeling within the otic capsule, similar to otosclerosis. These mice also develop progressive hearing loss, similar to cases of advanced otosclerosis. We have shown that bisphosphonates are highly effective in halting the pathologic remodeling and hearing loss in OPG-/- mice. We will now investigate effects of direct intracochlear and intratympanic delivery of risedronate, a potent bisphosphonate. We have chosen risedronate because of its high potency and availability of a fluorescein conjugated form of the drug that allows its quantification and localization. These experiments will guide the development of a bisphosphonate formulation for inner ear delivery in humans. If successful, these studies will lead quickly to clinical trials in humans with progressive sensorineural hearing loss from cochlear otosclerosis using a bisphosphonate-eluting stapes prosthesis, an intratympanic bisphosphonate formulation, or both. The development of this technology will also be valuable for other inner ear disorders that may benefit from direct drug delivery.

描述（申请人提供）：耳硬化是一种耳囊疾病，是获得性听力损失的最常见原因之一。在过去的15年里，我们的实验室一直致力于阐明耳硬化的分子病理学，并以发展更好的治疗形式为长期目标。这些研究为我们带来了一种新的创新治疗策略：通过药物洗脱聚合物的内耳输送双膦酸盐。我们已经开始开发和测试一种用于人类的药物配方，并开发了一种动物模型来测试它。由于大多数耳硬化患者接受镫骨假体，我们将聚合物整合到假体中用于耳蜗内输送。我们还将把聚合物集成到晶圆中，通过圆窗膜输送。耳囊的独特之处在于它通常很少或没有骨重塑。耳硬化的特征是耳囊的异常重塑。一些双膦酸盐化合物是骨重塑的有效抑制剂，但在人类全身给药时可能发生潜在的严重副作用，如抑制所有骨骼重塑和颌骨骨坏死。耳蜗内和鼓室内给药应绕过这些全身性问题，并确保药物以所需的形式和浓度到达耳蜗组织和耳囊。我们已经确定了一种动物模型，OPG-/-（敲除）小鼠，它在耳囊内表现出活跃重塑的病灶，类似于耳硬化。这些小鼠也会出现进行性听力丧失，类似于晚期耳硬化症。我们已经表明，双膦酸盐在阻止OPG-/-小鼠的病理性重塑和听力损失方面非常有效。我们现在将研究直接在耳蜗内和鼓室内给药利塞膦酸钠（一种有效的二磷酸盐）的效果。我们选择了利塞膦酸盐，因为它的高效和荧光素缀合形式的药物的可用性，允许其定量和定位。这些实验将指导用于人类内耳给药的双膦酸盐制剂的开发。如果成功，这些研究将很快引导临床试验，使用双膦酸盐洗脱镫骨假体，鼓室内双膦酸盐制剂，或两者兼而有之，用于耳蜗耳硬化导致的进行性感觉神经性听力损失患者。这项技术的发展对其他可能受益于直接给药的内耳疾病也很有价值。