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，是后天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。这些研究使我们找到了一种新的创新的治疗策略：通过药物洗脱聚合物内耳给药双膦酸盐。我们已经开始开发和测试一种用于人类的药物配方，并开发了一个动物模型来测试它。由于大多数耳硬化症患者都接受了月骨假体，我们将把聚合物整合到假体中，以便在耳廓内释放。我们还将把聚合物集成到晶片中，通过圆窗薄膜进行输送。耳囊是独一无二的，因为它通常很少或根本没有骨重塑。耳硬化症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，但全身给药可能会出现严重的副作用，如抑制所有骨骼重塑和颌骨坏死。耳廓内和鼓室内给药应该绕过这些全身问题，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-/-(基因敲除)小鼠，它在耳囊内表现出活跃的重塑灶，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的直接鼓膜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可获得的荧光素偶联形式的药物，使其能够量化和定位。这些实验将指导开发一种用于人类内耳递送的双膦酸盐配方。如果成功，这些研究将很快在人类中进行临床试验，这些人患有耳蜗性耳硬化症所致的进行性感音神经性听力损失，使用双膦酸盐洗脱距骨假体，或使用鼓室内双膦酸盐制剂，或两者兼而有之。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将是有价值的。

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.