Gene Therapy Delivery for Age-related Neurodegenerative Diseases

项目总结/摘要 阿尔茨海默病相关的神经退行性疾病，如阿尔茨海默病和相关的Tau蛋白病，是阿尔茨海默病的主要病因。 治疗挑战有一些关键的脑区与疾病的发病机制有关，随着时间的推移， 整个或大部分大脑都受到影响。因此，无论是局部还是广泛的脑治疗方法， 需要达到长期的治疗效果。基因治疗是利用遗传物质来靶向疾病 病因学病毒载体用于将治疗性基因递送至细胞，以提供来自免疫系统的持久干预。 单一治疗。重组腺相关病毒（rAAV）载体由于其高效的生物学特性而被广泛使用。 基因转移，广泛的依赖于基因型的向性，低风险的插入突变，和长期转基因 在非分裂细胞如神经元中表达。AAV 9是目前最常用的血清型， 治疗神经系统疾病，因为它可以在血液或脑脊髓液中输送， 以剂量依赖的方式影响大脑。直接脑注射对于局部脑治疗是有效的，但 侵入性手术在非侵入性全身递送的情况下，需要高载体剂量以实现足够的药物释放。 成年人的大脑传导接受的病毒颗粒数量越多， 免疫反应和抑制成人使用，由于生产的考虑。我们和其他人已经 证明使用FUS打开BBB可以显著降低全身载体剂量并靶向rAAV vectors向量to select选择brain脑regions区域.虽然有希望用于病灶治疗，但这限制了AAV 9的能力， 有效地覆盖非目标大脑区域。AAV 9的CSF递送显著降低了AAV 9的量。 与全身递送相比，需要载体实现等同或更大的脑转导， 相对于注射部位的高CNS转导。因此，我们预测，AAV 9的IT交付结合 经颅FUS将允许基因治疗对大脑的局部和广泛靶向， 治疗与年龄相关的神经退行性疾病的有效方法。这笔赠款将开发使用 组合的FUS和IT注射作为AAV载体向脑的有效递送方法，定义了机制 对于这种增强，确定载体衣壳和启动子的使用，并在小鼠模型中测试这种应用 tau蛋白病如果我们成功了，这种方法可以很容易地转化为治疗神经退行性疾病， 疾病

Project Summary/Abstract Age-related neurodegenerative disorders, such as Alzheimer’s disease and related tauopathies, are a major therapeutic challenge. There are critical brain regions implicated in disease pathogenesis and overtime the whole or a large portion of the brain is affected. Therefore, both a focal and broad brain treatment approach is needed to achieve long-term therapeutic benefit. Gene therapy is the use of genetic material to target disease etiology. Viral vectors are used to deliver therapeutic genes to cells to provide long-lasting intervention from a single treatment. Recombinant adeno-associated virus (rAAV) vectors are highly used due to their efficient gene transfer, broad serotype-dependent tropism, low risk of insertional mutagenesis, and long-term transgene expression in non-dividing cells, such as neurons. AAV9 is currently the most frequently used serotype for treating neurological disorders as it can be delivered in blood or cerebral spinal fluid to broadly transduce the brain in a dose-dependent manner. Direct brain injections are effective for focal brain treatments, but are an invasive procedure. With non-invasive systemic delivery, high vector doses are needed to achieve sufficient brain transduction in adults. The greater the number of viral particles received increases the risk of severe immune responses and inhibits use in adults due to manufacturing considerations. We and others have demonstrated that use of FUS to open the BBB can significantly reduce systemic vector doses and target rAAV vectors to select brain regions. While promising for focal treatments, this then limits the ability of AAV9 to efficiently transduce non-targeted brain regions. CSF delivery of AAV9 significantly reduces the amount of vector needed to achieve equivalent or greater brain transduction compared to systemic delivery and achieves high CNS transduction relative to the site of injection. Therefore, we predict that IT delivery of AAV9 combined with transcranial FUS will allow for both focal and broad targeting of gene therapies to the brain and be an effective delivery approach for age-related neurodegenerative diseases. This grant will develop the use of combined FUS and IT injection as an efficient delivery method of AAV vectors to the brain, define mechanisms for this enhancement, determine vector capsid and promoter usage, and test this application in a mouse model of tauopathy. If we are successful, this approach can be readily translated for treating neurodegenerative diseases.