Repurposing momelotinib for the prevention of aminoglycoside-induced ototoxicity

重新利用莫洛替尼预防氨基糖苷类引起的耳毒性

基本信息

批准号：
10341150
负责人：
Jonathan Paul Fleegel
金额：
$ 4.52万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341150
关键词：
ACVR1 gene Address Adult Adverse effects Age Aminoglycoside Antibiotics Aminoglycosides Animal Model Antibiotics Area Auditory Auditory Brainstem Responses Back Bacterial Infections Career Choice Cells Child Clinic Clinical Cochlea Communication Communities Cytoprotection Data Data Set Development Diagnosis Disease Disease Progression Drug usage Educational Curriculum Ensure Environment Equilibrium Evaluation Exposure to FDA approved Feeling Future Global Change Goals Gram-Negative Bacterial Infections Hair Cells Health Benefit Hearing Hearing Tests Hospitals Human Individual Infection Intervention Janus kinase Kanamycin Label Life Mediating Mental Depression Methods Mission Mus National Institute on Deafness and Other Communication Disorders Neonatal Intensive Care Units Otolaryngology Outer Hair Cells Pathogenesis Patients Pharmaceutical Preparations Physicians Prevention Preventive treatment Process Property Public Health Publishing RNA Sequences Recording of previous events Research Research Project Grants Research Training Risk Scientist Sensory Hair Sepsis Septicemia Strategic Planning Students Techniques Technology Therapeutic Therapeutic Agents Time Toxic effect Training Tyrosine Kinase Receptor Inhibition Universities World Health Organization Zebrafish aminoglycoside-induced ototoxicity base cell injury clinically relevant combat cost drug candidate drug repurposing experience experimental study hair cell regeneration hearing impairment hearing restoration improved in silico in vivo inhibitor knock-down molecular drug target mouse model neonate novel otoacoustic emission otoprotectant ototoxicity pre-clinical preclinical study prevent prevent hearing loss programs protective effect response screening side effect single cell sequencing systemic toxicity therapy development transcriptome

项目摘要

PROJECT SUMMARY: Aminoglycoside antibiotics are considered an essential group of medications by the World Health Organization. Each year, thousands of children and adults are prescribed aminoglycosides to treat severe gram-negative bacterial infections. This is especially prominent in the neonatal intensive care units, where over 80% of the neonates are prescribed aminoglycosides. Unfortunately, administration of aminoglycosides carries substantial risk for life altering side effects, namely irreversible hearing loss. This is especially evident in the fact that 15 out of every 100 neonates will experience hearing loss, as compared to the 1 to 3 out of every 1,000 babies who are born full term. Hearing loss alters an individual’s ability to communicate and is associated with feelings of isolation and depression. Substantial effort is still required to identify the first FDA approved therapeutic for prevention of aminoglycoside related ototoxicity. We are proposing this study with the long-term goal of providing a therapeutic to combat this ototoxic side effect. To date, we have collected promising preliminary data suggesting momelotinib, a drug currently with FDA fast track designation, could be repurposed for this use. In Aim 1, we will use an aminoglycoside treated sepsis mouse model to provide preclinical, functional hearing data on the ability of momelotinib to prevent aminoglycoside induced hearing loss. In our experiments proposed in Aim 2, we will utilize the well-established and translatable zebrafish model organism to identify the essential targets and mechanisms of hair cell protection by momelotinib. This project advances the mission of the NIDCD to promote interventions to treat communication and other disorders. Specifically, our mechanistic studies in Aim 2 address Priority Area 2 in Hearing and Balance Research to increase the understanding and pathogenesis of ototoxicity. In addition, our characterization of momelotinib as a promising preventative treatment for aminoglycoside induced hearing loss advances Priority Area 3, to improve the diagnosis, treatment, and prevention of hearing loss through the development therapies to resist cell damage. This project will be completed at Creighton University under the sponsorship of the well-established auditory scientist, Dr. Jian Zuo. Creighton University has a strong history of auditory research. It houses a Translational Hearing Center dedicated to research pursuits in the therapeutic prevention of hearing loss and hearing restoration through hair cell regeneration. The physician-scientist program at Creighton University provides a well-rounded, integrated curriculum and tailors educational and clinical experiences to each student and their career aspirations. Specifically, the gateway program and longitudinal clinic provide great opportunities for students to gain exposure to the field they are going to enter. There is also a clinical refresher course offered during the last year of research training, which will ease the transition of the students back into the clinic. Overall, the strong auditory research community, unique training environment and impactful research project, ensures that my time at Creighton University will facilitate my development to become an independent physician-scientist in the field of otolaryngology.

项目概要：世界卫生组织认为氨基糖苷类抗生素是一组重要的药物。每年，成千上万的儿童和成人服用氨基糖苷类药物来治疗严重的革兰氏阴性菌这在新生儿重症监护室尤为突出，其中超过 80% 的新生儿都患有细菌感染。不幸的是，给新生儿服用氨基糖苷类药物会产生大量的副作用。改变生命的副作用，即不可逆转的听力损失，这一点在 15 例中尤为明显。每 100 名新生儿中就有 1 人会出现听力损失，而每 1,000 名婴儿中就有 1 至 3 人患有听力损失足月出生的听力损失会改变一个人的沟通能力，并与孤独感相关。仍需要付出大量努力来确定第一个 FDA 批准的预防抑郁症的治疗方法。我们提出这项研究的长期目标是提供一种治疗方法。为了对抗这种耳毒性副作用，迄今为止，我们已经收集了有希望的初步数据。莫莫替尼（momelotinib）是一种目前获得 FDA 快速通道指定的药物，可以重新用于这一用途。将使用氨基糖苷类治疗的脓毒症小鼠模型来提供临床前、功能性听力数据在我们目标 2 中提出的实验中，莫莫替尼预防氨基糖苷类引起的听力损失的能力。我们将利用成熟且可翻译的斑马鱼模型生物来确定基本目标和该项目推进了 NIDCD 促进毛细胞保护的使命。具体来说，我们的目标 2 中的机制研究涉及治疗沟通和其他障碍的干预措施。听力和平衡研究优先领域 2，以增进对耳毒性的理解和发病机制。此外，我们将莫洛替尼描述为一种有前景的氨基糖苷类预防性治疗方法诱发性听力损失优先领域 3，改善听力的诊断、治疗和预防通过开发疗法来抵抗细胞损伤。该项目将在 Creighton 完成。由著名听觉科学家左健博士赞助的大学。它拥有悠久的听觉研究历史，设有致力于研究的转化听力中心。通过毛细胞再生来治疗性预防听力损失和恢复听力。克赖顿大学的医师科学家项目提供全面、综合的课程和定制课程具体来说，是每个学生的教育和临床经验以及他们的职业抱负。项目和纵向诊所为学生提供了接触他们所在领域的绝佳机会在最后一年的研究培训中还提供了临床进修课程。总体而言，强大的听觉研究社区将帮助学生轻松过渡到临床。独特的培训环境和有影响力的研究项目，确保我在克赖顿大学的时光促进我发展成为耳鼻喉科领域的独立医师科学家。