Cochlear Therapy through Magnetic Targeted Drug Delivery

描述（由申请人提供）：感音神经性听力损失（SNHL）是影响3000多万美国人的最常见的耳聋类型，在很大程度上无法治疗。当毛细胞死亡时，螺旋神经节神经元也可能失去其外周轴突并退化。 在鸟类中，而不是哺乳动物中，支持细胞重新进入细胞周期，分裂并分化成新的毛细胞。 第一次在哺乳动物中完成了从受损耳蜗中残留的非感觉细胞再生毛细胞的有前途的基因治疗。 基因Atoh 1（Math-1）诱导支持细胞取代毛细胞，并恢复听力（听觉脑干反应）。 该项目旨在证明多功能纳米颗粒（MFNP）靶向递送系统的有效性，该系统利用磁力将不同的治疗有效载荷（如Atoh 1）递送至哺乳动物耳蜗。 我们的研究团队寻求建立在坚实的基础和试点数据，以完善我们的SNHL治疗方法，以转化为临床治疗机会。 研究的第一部分将表征三种MFNP载体，并在细胞培养和啮齿动物模型中测试它们的膜转运和靶向。 将通过使用放射性核素示踪、DNA、蛋白质和色谱分析来实现MFNP递送量的定量。 该项目的第二部分将在中毒和毒素损伤的小鼠耳蜗培养中证明治疗效果。 通过非病毒载体在耳蜗中的转染将是一个重要的里程碑。 本研究的第三部分将采用MFNP及其三种治疗有效载荷进行下一步临床用途：递送至人类耳蜗。 尸体的颞骨将用于测试MFNP的输送。 同样，将使用放射性核素示踪方法来量化有多少MFNP有效载荷可以通过限定的外部磁场及时递送。 这些目标的成功实现将验证这项技术，并为下一步的临床开发做好准备，例如啮齿动物体内治疗实验。 将治疗性纳米颗粒磁性靶向到耳朵可能会导致一种安全、有效和高效的方法，通过预防听力损失甚至恢复听力损失来治疗SNHL和其他内耳疾病患者。 公共卫生相关性：感音神经性听力损失（SNHL）是影响3000多万美国人的最常见的耳聋类型，是由遗传疾病，年龄，噪音，感染和毒素引起的毛细胞死亡引起的。 SNHL虽然可以用设备治疗，但在很大程度上无法治疗，每年花费美国公众超过560 B美元。 该研究项目旨在开发治疗性纳米颗粒的磁性靶向耳朵，可能会导致一种安全，有效和高效的方法，通过预防听力损失甚至恢复听力来治疗患有SNHL的患者。

DESCRIPTION (provided by applicant): Sensorineural hearing loss (SNHL), the most common type of deafness affecting more than 30 million Americans, is largely untreatable . When hair cells die, spiral ganglion neurons also may lose their peripheral axons and degenerate. In birds, but not mammals, supporting cells re-enter the cell cycle, divide and differentiate into new hair cells. A promising gene therapy for hair cell regeneration from non-sensory cells that remain in damaged cochlea has been accomplished in mammals for the first time. The gene Atoh 1 (Math-1) induced replacement of hair cells from supporting cells and restored hearing (auditory brainstem responses) in deafened mammals. This project seeks to demonstrate the efficacy of a multi functional nanoparticle (MFNP) targeted delivery system utilizing magnetic forces for delivery of distinct therapeutic payloads, such as Atoh 1 to the mammalian cochlea. Our research team seeks to build upon a solid foundation and pilot data to refine our treatment approaches for SNHL for translation to clinical treatment opportunities. The first segment of the study will characterize the three MFNP carriers and test them for membrane transport and targeting in both cell culture and rodent models. Quantification of the amount of MFNP delivered will be accomplished by using radionuclide tracing, DNA, protein and chromatographic analyses. The second part of the project will demonstrate therapeutic effectiveness in deafened and toxin-injured mouse cochlear cultures. Transfection in the cochlea by a non-viral vector would be a major milestone. The third portion of this study will take the MFNP with it three therapeutic payloads to the next step toward clinical use: delivery to the human cochlea. Temporal bones from cadavers will be used to test delivery of the MFNP. Again, a radionuclide tracing method will be used to quantify how much of the MFNP-payload can be delivered in time by a defined external magnetic field. Successful accomplishment of these aims will validate this technology and prepare for the next step toward clinical development, such as in vivo therapeutic experiments rodents. Magnetic targeting of therapeutic nanoparticles to the ear may lead to a safe, effective and efficient means of treating patients with SNHL and other inner ear disorders by preventing hearing loss and perhaps even restoring lost hearing. PUBLIC HEALTH RELEVANCE: Sensorineural hearing loss (SNHL), the most common type of deafness affecting more than 30 million Americans, is caused by death of hair cells from genetic disorders, age, noise, infection and toxins. SNHL, although amenable to habilitation with devices, is largely untreatable and costs the U.S. public more than $56 B annually. This research project, to develop magnetic targeting of therapeutic nanoparticles to the ear, may lead to a safe, effective and efficient means of treating patients who suffer from SNHL by preventing hearing loss or perhaps even restoring lost hearing.