Drug Delivery Method for Sudden Sensorineural Hearing Loss

描述（由申请人提供）：拟议项目的最终目标是评估和商业化专有磁铁组件和磁性纳米颗粒的组合（最初由我们的大学STTR合作伙伴开发），该组合已在初步动物研究中显示，可改善药物向内耳的输送。使用该系统（利用磁力将类固醇洗脱的磁性纳米颗粒注入内耳）进行的初步动物研究已经成功地降低了大鼠因听觉创伤而导致的听力损失和耳鸣的程度。这些初步研究表明，到达内耳的类固醇量增加了十倍（与目前经鼓室注射到中耳的标准相比），没有副作用。我们的战略是展示磁性注射系统作为平台技术的实用性，解决40亿美元的听力市场，从目前无法治愈的令人信服的临床问题开始。突发性感音神经性听力损失（SSHL）是一种孤儿病，既没有明确的病因，也没有令人满意的治疗方法，被认为是耳科急症。目前的治疗方法，包括口服和经鼓室类固醇注射到中耳，只是部分有效。目前还没有一种被广泛认可的SSHL动物模型，因此，监管专家建议我们，在显示出改善的动物给药和安全性之后，我们需要直接进行研究性新药（IND）的人体试验申请。我们计划在STTR项目的I期进行原理验证和毒性研究，然后在STTR项目的II期进行全面的药物动力学研究，为IND做准备。目前SSHL的治疗标准是向中耳注射类固醇。我们期望临床前证明其低毒性

DESCRIPTION (provided by applicant): The ultimate goal of the proposed project is to evaluate and commercialize a combination of proprietary magnet assemblies and magnetic nanoparticles (initially developed by our University STTR partner), that has been shown in preliminary animal studies to improve delivery of medications to the inner ear. Initial animal studies using the system (which uses magnetic forces to inject steroid-eluting magnetic nano-particles into the inner ear) have successfully reduced the degree of hearing loss and tinnitus in rats due to acoustic trauma. These initial studies suggest that the amount of steroids reaching the inner ear is increased ten-fold (compared to the current standard of trans-tympanic injection into the middle ear), without side effects. Our strategy is to demonstrate the utility of the magnetic injection system as a platform technology addressing the $4 billion hearing market, starting with a compelling clinical problem that currently is without a cure. Sudden Sensorineural Hearing Loss (SSHL) is an orphan disease without either a clear cause or a satisfactory therapy, and is considered to be an otologic emergency. Current therapies, which include oral and trans- tympanic steroid injection into the middle ear, are only partially effective. There is n widely-recognized animal model for SSHL, and as a result, we have been advised by regulatory experts that we would need to proceed directly to an investigational new drug (IND) application for human testing after showing improved drug delivery and safety in animals. We plan to advance in step-wise fashion by performing proof-of-principle and toxicity studies in the Phase I portion of the STTR project, and then conducting comprehensive pharmaco- kinetic studies in the STTR Phase II portion in preparation for the IND. The current standard of care in SSHL is to inject steroids into the middle ear. We expect that with preclinical demonstrations of low toxicity and high delivered more-uniform inner-ear concentrations using the magnetic injection system, the FDA would approve an IND augmenting trans-tympanic needle injections with magnetic injection of drug-eluting particles. Eventually we anticipate that the magnetic injection platform technology will be approved for other ear, nose and throat and CNS conditions. In Phase I, we will demonstrate the superiority of magnetic injection in attaining and maintaining physiologically-effective concentration of active ingredient in the inner ear (with low serum concentration). We will collect toxicity data for expected levels of steroid-loaded nanoparticles, quantifying levels of apoptotic and inflammatory responses in-vitro. With animal studies we will show significantly improved drug delivery and cochlear drug uniformity, and will demonstrate non-significant incidences of morbidity, mortality, and ototoxicity in-vivo. In Phase II, we will attempt to conduct rigorous pharmacokinetic studies and work with a strategic partner in the (fairly profitable) Orphan drug market, in preparation for IND submission.