Development of Genome Editing as Treatment for Genetic Hearing Loss

项目摘要和相关性 包括阿尔茨海默病(AD)在内的痴呆症在老龄化人口中表现出来，但所有的临床试验 多年来未能阻止或纠正疾病的发展。疾病的流行 随着年龄的增长而增加，并将在未来成为更大的负担，因为 全球人口老龄化。研究表明感觉障碍之间存在联系，如 老年人的听力、视觉和嗅觉障碍与认知能力下降，尽管这些 关联是复杂的，可以表现出双向性。已经提出了几种假设的机制 例如共同的病理生理学或感觉缺陷和 痴呆症和阿尔茨海默氏症。然而，仍有待确定是否以及在多大程度上 听力损失会导致痴呆症或阿尔茨海默氏症，如果恢复听力可以减轻疾病 表型。最近，听力损失被认为是最大的可改变的因素之一 痴呆症和阿尔茨海默病的危险因素。听力损失的小鼠模型的可用性和 AD使直接评估在年轻或成年时表现出的听力损失是否有助于 关于功能和结构措施的广告。在本管理补充资料中，我们将利用我们的 致力于编辑治疗方法以治疗遗传性耳聋小鼠模型，这是由于基因突变 Pmca2(Atp2b2)基因和microRNA mir96来确定Pmca2小鼠和 Mir96小鼠的进行性听力损失与阿尔茨海默病的表型有关 AD小鼠模型(5xFAD和3xTg-AD，由于人类APP和PSEN1转基因的表达)。这 将通过将Pmca2和Mir96突变引入AD背景并研究是否 行为中的AD表型(空间工作记忆、学习障碍、皮层依赖遥控器 记忆、恐惧条件反射和运动障碍)会因听力损失而加重。细胞事件 包括星形胶质细胞增多症和小胶质细胞增多症，突触变性和神经元丢失也将被比较。我们的 正在进行的R01研究表明，编辑疗法有力地挽救了Pmca2小鼠的听力，并 我们已经对sgRNA进行了优化，以编辑mir96突变来挽救听力。通过选择听力损失 通过编辑治疗可以成功治疗的模型，我们将确定听力恢复是否会导致 延缓AD表型的进展。这项研究将提供对这一机制的洞察 听力损失和阿尔茨海默病之间的相互作用，并建立 阿尔茨海默病进展的个性化听力损失治疗。

Project Summary and Relevance Dementia including Alzheimer’s disease (AD) is manifested in aging population, yet all the clinical trials over the years failed to halt or revise the progression of the diseases. The prevalence of the diseases increases with age and will present as ever larger burden in future given the disproportional increase in aging population worldwide. Studies have suggested an association between sensory disorders such as hearing, visual, and olfactory impairments with cognitive decline in older adults although these associations are complex and can exhibit bidirectionality. Several hypothetical mechanisms have been proposed, such as a common pathophysiology or a cause-effect relationship between sensory deficits and dementia and Alzheimer’s disease. However, it remains to be determined if and the extent to which hearing loss contributes to dementia or Alzheimer’s disease and if rescue of hearing could lessen disease phenotypes. Recently hearing loss has been hypothesized to play a role as one of the largest modifiable risk factors for dementia and Alzheimer’s disease. The availability of mouse models for hearing loss and AD makes it possible to directly evaluate if hearing loss, manifested in young or adult age, contributes to AD on the functional and structural measures. In this administration supplement, we will leverage our work in editing therapy to treat genetic deafness mouse models due to dominant mutations in the Pmca2(Atp2b2)gene and microRNA mir96 to establish if early onset hearing loss in the Pmca2 mice and progressive hearing loss in the mir96 mice contribute to AD disease phenotype in two well-characterized AD mouse models (5xFAD and 3xTg-AD, due to expression of human APP and PSEN1 transgenes). This will be done by introducing Pmca2 and Mir96 mutations into the AD background and by studying if the AD phenotypes in behavior (spatial working memory, impaired learning, cortex-dependent remote memory, fear conditioning and motor impairment) is exacerbated by hearing loss. Cellular events including astrogliosis and microgliosis, synaptic degeneration and neuron loss will also be compared. Our ongoing R01 work has demonstrated that editing therapy robustly rescues hearing in the Pmca2 mice and we have optimized sgRNA to editing the mir96 mutation to rescue hearing. By selecting hearing loss models that can be treated successfully by editing therapy, we will determine if hearing rescue leads to lessening of the progression of the AD phenotypes. The study will provide the insight into the mechanism of interactions between hearing loss and Alzheimer’s disease, and to establish the potential of personalized hearing loss therapy on the progression of Alzheimer’s disease.