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Virally Mediated Gene Therapy for Genetic Hearing Loss

病毒介导的基因治疗遗传性听力损失

基本信息

批准号：
8401151
负责人：
LAWRENCE R LUSTIG
金额：
$ 19.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-16 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401151
关键词：
Ablation Affect Area Birth Child Clinical Trials Cochlea Cochlear implant procedure Disease Electron Microscopy Evoked Potentials, Auditory, Brain Stem Foundations Future Gene Delivery Genes Genetic Glutamates Goals Hearing Hearing Impaired Persons Histologic Human Human Genetics Immunofluorescence Immunologic Immunologic Deficiency Syndromes Incentives Inherited Investigation Knock-out Knockout Mice Labyrinth Liquid substance Mediating Methods Modeling Mus Natural regeneration OTOF gene Operative Surgical Procedures Pathologic Pattern Phenotype Physiology Property Reflex action Regimen Research Proposals Resort SLC17A8 gene Series Structure Synapses Synaptic Transmission Techniques Time Transgenic Mice Viral Work adeno-associated viral vector congenital deafness deafness gene therapy hair cell regeneration hearing impairment light microscopy mouse model novel otoacoustic emission postnatal public health relevance restoration spiral ganglion success viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): Approximately 1.5 in 1000 children are affected by deafness at birth, 1/2 of which can be attributed to a genetic cause. Treatment for these inherited forms of deafness is quite limited, and consists of hearing amplification for mild to severe hearing loss, and cochlear implantation for severe to profound hearing loss. Gene therapy has been suggested as a potential treatment for genetic hearing loss, but success in this area has remained elusive. Important advances have been made towards hair cell regeneration using virally-mediated gene delivery; however breakthroughs in cellular regeneration likely would not benefit those with genetic deafness because the underlying genetic background would be unchanged. Yet the inner ear remains an attractive target for gene therapy due to advances in surgical access and confinement of fluid space by the bony structure of the cochlea. We have been studying a transgenic mouse that is profoundly deaf after deletion of the vesicular glutamate transporter-3 (VGLUT3) gene, the same gene responsible for the human non-syndromic deafness DFNA25. Our recent work has led to successful restoration of hearing in postnatal mice by local monogenic therapy using an adeno- associated viral vector (AAV-VGLUT3). This novel initial finding provides a powerful incentive to investigation if this therapy can be optimized and generalized to other forms of genetic deafness. The overall goals of this proposal are to optimize the viral-gene delivery method to the cochlea for hearing restoration in the VGLUT3 knockout (KO) mouse, verify that normal synaptic physiology is restored, and determine whether this technique can be generalized to another mouse model of genetic deafness, the otoferlin knockout mouse, a model for the human genetic deafness DFNB9. Results from these studies may provide the foundation for future clinical trials in humans with some forms of genetic deafness.

描述（由申请人提供）：每1000名儿童中约有1.5名在出生时受到耳聋的影响，其中1/2可归因于遗传原因。对这些遗传性耳聋的治疗非常有限，包括轻度至重度听力损失的听力放大和重度至极重度听力损失的人工耳蜗植入。基因治疗已被认为是遗传性听力损失的潜在治疗方法，但在这一领域的成功仍然难以捉摸。使用病毒介导的基因递送在毛细胞再生方面取得了重要进展;然而，细胞再生的突破可能不会使遗传性耳聋患者受益，因为潜在的遗传背景不会改变。然而，内耳仍然是一个有吸引力的目标，基因治疗由于先进的手术进入和限制流体空间的骨结构的耳蜗。我们一直在研究一种转基因小鼠，它在缺失囊泡谷氨酸转运蛋白3（VGLUT 3）基因后严重失聪，该基因与人类非综合征性耳聋DFNA 25相同。我们最近的工作已经通过使用腺相关病毒载体（AAV-VGLUT 3）的局部单基因疗法成功地恢复了出生后小鼠的听力。这一新的初步发现提供了一个强大的激励调查，如果这种疗法可以优化和推广到其他形式的遗传性耳聋。该提案的总体目标是优化VGLUT 3敲除（KO）小鼠耳蜗听力恢复的病毒基因递送方法，验证恢复正常的突触生理学，并确定该技术是否可以推广到另一种遗传性耳聋的小鼠模型，otoferlin敲除小鼠，人类遗传性耳聋DFNB 9的模型。这些研究的结果可能为未来在某些形式的遗传性耳聋患者中进行临床试验提供基础。