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

描述（由申请人提供）：耳硬化症是一种耳囊疾病，是获得性听力损失的最常见原因之一。在过去的十五年里，我们的实验室一直致力于阐明耳硬化症的分子病理学，长期目标是开发更好的治疗方法。这些研究使我们产生了一种新的和创新的治疗策略：通过药物洗脱聚合物内耳递送双膦酸盐。我们已经开始开发和测试用于人类的药物配方，并开发了一种动物模型来测试它。由于大多数耳硬化症患者接受镫骨假体，我们将聚合物整合到假体中进行耳内输送。我们还将聚合物集成到晶片中，以便通过圆窗膜传递。耳囊是独特的，因为它通常表现出很少或没有骨重建。耳硬化症的特征在于耳囊的异常重塑。一些双膦酸盐化合物是骨重塑的有效抑制剂，但在人体中全身给药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系统性问题，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，其表现出耳囊内的主动重塑病灶，类似于耳硬化症。这些小鼠也会出现进行性听力损失，类似于晚期耳硬化症。我们已经证明，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。我们现在将研究利塞膦酸盐（一种有效的双膦酸盐）直接颅内和鼓室内给药的效果。我们选择利塞膦酸盐是因为它的高效力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递送的双膦酸盐制剂的开发。如果成功的话，这些研究将很快导致临床试验，在人类进行性感音神经性听力损失的耳蜗耳硬化症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。这项技术的发展也将对其他可能受益于直接药物输送的内耳疾病有价值。 公共卫生相关性：如果成功的话，这些研究将直接导致临床试验，在人类进行性感音神经性听力损失的耳蜗耳硬化症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，使用安全和完善的中耳手术技术。这项技术的发展也将对其他可能受益于直接药物输送的内耳疾病有价值。

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. PUBLIC HEALTH RELEVANCE: If successful, these studies will lead directly 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, using safe and well-established techniques of middle ear surgery. The development of this technology will also be valuable for other inner ear disorders that may benefit from direct drug delivery.