Spiral Ganglion Health: from Genomics to Gene Therapy

螺旋神经节健康：从基因组学到基因治疗

• 批准号: 10626894
• 负责人: Aiden Eliot Shearer
• 金额: $ 19.3万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626894
• 关键词: Acoustic Nerve; Adult; Affect; Applications Grants; Bypass; CRISPR/Cas technology; Calcium; Cell Death; Child; Childhood; Clinical; Cochlea; Cochlear Implants; Cochlear implant procedure; Complex; DNA Sequence Alteration; Data; Development; Electrocochleographies; Funding; Future; Gene therapy trial; Genes; Genetic; Genetic Risk; Genetic Variation; Genomics; Genotype; Goals; Grant; Hair Cells; Health; Hearing; Hearing Aids; Human; Human Genetics; In Vitro; Individual; Inner Hair Cells; Knockout Mice; Language Development; Lead; Methods; Mus; Mutation; Neurons; Newborn Infant; Operative Surgical Procedures; Organ of Corti; Outcome; Outer Hair Cells; Patients; Pediatric cohort; Phenotype; Postoperative Care; Postoperative Period; Potassium Channel; Proteins; Quality of life; Research; Risk; Role; Scientist; Sensory Disorders; Serine Protease; Social Development; Speech; Speech Development; Speech Perception; Statistical Models; Surgeon; Synapsins; Testing; Time; Training; Variant; alternative treatment; autosome; career; childhood hearing loss; congenital hearing loss; deaf; deafness; effective therapy; experience; experimental study; functional restoration; gene therapy; hearing impairment; hearing restoration; hereditary hearing loss; human genomics; improved; in vivo; indexing; innovation; language outcome; large-conductance calcium-activated potassium channels; mouse model; negative affect; novel; novel therapeutic intervention; preoperative counseling; progressive hearing loss; promoter; sensory prosthesis; single-cell RNA sequencing; spiral ganglion; vector

PROJECT ABSTRACT Congenital hearing loss affects 1 in 500 newborns, making it the most common sensory disorder in humans. Children with hearing loss are at risk for poor speech, language, and social development with noted negative effects on quality of life. The most effective treatment for severe-to-profound hearing loss in children is cochlear implantation. The cochlear implant (CI) is the most successful and widely used sensory prosthesis in humans and cochlear implantation has restored hearing to hundreds of thousands around the world. While the majority of CI users experience significant improvement in speech perception, a significant portion do not. There is a critical need to identify individuals at-risk for poor outcomes prior to cochlear implantation in order to: (1) provide accurate pre-operative counseling, (2) tailor post-operative care, and (3) develop new treatment strategies for these types of hearing loss. To date, the best predictors of CI speech perception outcomes rely on complex statistical modeling of clinical factors associated with hearing loss or intra-operative electrocochleography (ECoG), neither of which can be routinely used pre-operatively. There is increasing evidence that specific genetic variations that negatively affect the health of spiral ganglion neurons (SGNs) are associated with worse postoperative CI speech perception outcomes. The primary goal of this grant proposal is to better understand genetic contributors to postoperative speech perception outcomes in children. We recently showed that variations in the gene TMPRSS3 are associated with worse CI speech perception outcomes. Although TMPRSS3 is one of the most common causes of genetic hearing loss, the function of the TMPRSS3 protein and the mechanism by which it causes hearing loss are not known. TMPRSS3 is involved in expression of calcium- sensitive potassium channels in inner hair cells. A knock-out mouse model shows rapid hair cell degeneration soon after the onset of hearing. However, deafness-causing mutations in TMPRSS3 are notable for causing not only a severe-to-profound congenital hearing loss (DFNB10) but also a later onset post-lingual hearing loss (DFNB8). In addition, the expression of TMPRSS3 includes hair cells and also SGNs. We hypothesize that TMPRSS3 has functions in the inner hair cells as well as in the SGN. The aims of this project are to: (1) examine the complex interplay between genetics, ECoG, and post-operative speech perception scores in children with CIs, (2) improve our understanding of TMPRSS3 through development of a new mouse model for late onset DFNB8 hearing loss, and (3) develop a new gene therapy for TMPRSS3 hearing loss. The expected results of this study will be: (1) a genetic risk index for poor CI outcomes in children, (2) a better understanding of the function of TMPRSS3 in hearing and hearing loss, and (3) a novel gene therapy for TMPRSS3 hearing loss. The results of this study will have direct clinical impact as well as pave the way for future gene therapy trials in humans.

项目摘要 先天性听力损失影响500个新生儿中的1个，使其成为人类最常见的感觉障碍。 听力损失儿童的言语、语言和社交能力发展都有不良的风险， 对生活质量的影响儿童重度至极重度听力损失最有效的治疗方法是耳蜗 置入人工耳蜗是目前应用最广泛、最成功的感觉器官 人工耳蜗植入已经使全世界成千上万的人恢复了听力。虽然大多数 的CI用户在语音感知方面经历了显著的改善，很大一部分没有。有一个 迫切需要在人工耳蜗植入前识别有不良结局风险的个体，以便：（1）提供 准确的术前咨询，（2）定制术后护理，（3）制定新的治疗策略， 这些类型的听力损失到目前为止，CI语音感知结果的最佳预测因素依赖于复杂的 与听力损失或术中耳蜗电描记术相关的临床因素的统计建模 （ECoG），两者都不能在术前常规使用。越来越多的证据表明， 对螺旋神经节神经元（SGN）健康产生负面影响的变异与更差的 术后CI语音感知结果。这项拨款提案的主要目标是更好地了解 儿童术后言语感知结果的遗传因素。我们最近发现， 基因TMPRSS 3的变异与更差的CI言语感知结果相关。虽然 TMPRSS 3是遗传性听力损失最常见的原因之一，TMPRSS 3蛋白的功能和 其导致听力损失的机制尚不清楚。TMPRSS 3参与钙离子的表达， 内毛细胞中敏感的钾通道。基因敲除小鼠模型显示毛细胞快速退化 在听力开始后不久。然而，TMPRSS 3中引起肥胖的突变是值得注意的， 不仅有重度至极重度先天性听力损失（DFNB 10），还有晚发性语后听力损失 （DFNB 8）。此外，TMPRSS 3的表达包括毛细胞以及SGN。我们假设 TMPRSS 3在内毛细胞以及SGN中具有功能。本项目的目标是：（1）研究 遗传学、ECoG和术后言语感知评分之间的复杂相互作用 CI，（2）通过开发一种新的迟发性TMPRSS 3小鼠模型， DFNB 8基因治疗耳聋的研究;（3）开发TMPRSS 3基因治疗耳聋的新方法。的预期结果 这项研究将是：（1）儿童CI不良结局的遗传风险指数，（2）更好地了解 TMPRSS 3在听力和听力损失中的功能;（3）TMPRSS 3听力损失的新基因治疗。的 这项研究的结果将具有直接的临床影响，并为未来的基因治疗试验铺平道路。 人类