Cochlear Therapy through Magnetic Targeted Drug Delivery

描述（由申请人提供）：感觉神经性听力损失（SNHL）是影响超过3000万美国人的最常见的耳聋类型，在很大程度上是无法治疗的。当毛细胞死亡时，螺旋神经节神经元也可能失去外周轴突并退化。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。研究人员首次在哺乳动物耳蜗中完成了一项很有前景的基因治疗，即从受损耳蜗中保留的非感觉细胞中再生毛细胞。基因Atoh 1 （Math-1）诱导耳聋哺乳动物的毛细胞从支持细胞中替换并恢复听力（听觉脑干反应）。该项目旨在证明多功能纳米颗粒（MFNP）靶向递送系统的功效，该系统利用磁力将不同的治疗有效载荷（如Atoh 1）递送到哺乳动物耳蜗。我们的研究团队寻求建立在坚实的基础和试点数据，以完善我们的治疗方法SNHL转化为临床治疗机会。研究的第一部分将描述三种MFNP载体的特征，并在细胞培养和啮齿动物模型中测试它们的膜运输和靶向性。MFNP递送量的定量将通过使用放射性核素示踪、DNA、蛋白质和色谱分析来完成。该项目的第二部分将证明耳聋和毒素损伤小鼠耳蜗培养的治疗效果。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把MFNP和它的三个治疗有效载荷带到临床应用的下一步：给人耳蜗。尸体的颞骨将被用来测试MFNP的输送。同样，将使用放射性核素示踪方法来量化在确定的外部磁场下mfnp有效载荷可以及时交付的量。这些目标的成功实现将验证这项技术，并为下一步的临床发展做好准备，例如在啮齿动物体内的治疗实验。磁性靶向治疗性纳米颗粒的耳朵可能会导致一种安全、有效和高效的方法来治疗SNHL患者和其他内耳疾病，防止听力损失，甚至可能恢复听力损失。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虽然可以通过设备进行康复治疗，但在很大程度上是无法治疗的，每年给美国公众造成的损失超过560亿美元。该研究项目旨在开发磁性靶向治疗性纳米颗粒到耳朵，可能会导致一种安全、有效和高效的方法来治疗SNHL患者，防止听力丧失，甚至可能恢复听力。

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.