Gene Therapy Delivery for Age-related Neurodegenerative Diseases

年龄相关神经退行性疾病的基因治疗

• 批准号: 10658771
• 负责人: Rachel M Bailey
• 金额: $ 73.62万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658771
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Animal Model; Animals; Biochemical; Blood; Blood - brain barrier anatomy; Brain; Brain region; Capsid; Cells; Cephalic; Cerebrospinal Fluid; Clinical Treatment; Clinical Trials; Coupled; Data; Dependovirus; Disease; Distal; Dose; Engineering; Etiology; Exposure to; Focused Ultrasound; Gene Delivery; Gene Transfer; Genetic Materials; Goals; Grant; Hepatotoxicity; Histopathology; Human; Immune response; Immunize; Injections; Insertional Mutagenesis; Interphase Cell; Intervention; Intrathecal Injections; Intravenous; Kinetics; Mediating; Methods; MicroRNAs; Mus; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathologic; Procedures; Recombinant adeno-associated virus (rAAV); Research; Risk; Route; Safety; Serotyping; Site; Specificity; Spinal Cord; Spinal Ganglia; Tauopathies; Testing; Therapeutic; Toxic effect; Translating; Trauma; Tropism; Viral; Viral Vector; Weight; Work; adeno-associated viral vector; age related neurodegeneration; behavior test; blood-brain barrier crossing; blood-brain barrier disruption; brain parenchyma; cost; cranium; delivery vehicle; gene therapy; hindbrain; improved; knock-down; manufacture; mouse model; nervous system disorder; neutralizing antibody; novel; novel strategies; particle; promoter; tau Proteins; tau mutation; therapeutic gene; therapeutically effective; therapy outcome; transduction efficiency; transgene expression; vector

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.

项目摘要/摘要 与年龄有关的神经退行性疾病，例如阿尔茨海默氏病和相关的tauopathies，是一个主要的 治疗挑战。在疾病发病机理和加时赛中实施了关键的大脑区域 全部或大部分大脑受到影响。因此，局灶性和广泛的大脑治疗方法是 需要实现长期治疗益处。基因治疗是将遗传物质用于靶向疾病 病因。病毒载体用于向细胞传递热基因，以提供持久的干预措施 单一治疗。重组腺相关病毒（RAAV）载体由于其有效而高度使用 基因转移，广泛的血清型依赖性偏移，插入诱变的低风险和长期转化 在非分裂细胞中的表达，例如神经元。 AAV9当前是最常用的血清型 治疗神经系统疾病，因为它可以用血液或脑脊髓液递送以广泛转导 大脑以剂量依赖性方式。直接大脑注射对于局灶性脑部治疗有效，但 侵入性程序。通过非侵入性的全身传递，需要高矢量剂量以实现足够的 成人的大脑转导。病毒颗粒的数量越大，会增加严重的风险 由于制造考虑因素，免疫反应和抑制成人的使用。我们和其他人有 证明使用FUS打开BBB可以显着降低全身矢量剂量并靶向RAAV 选择大脑区域的向量。虽然对焦点治疗的承诺，但这又限制了AAV9的能力 有效地翻译非目标的大脑区域。 CSF的AAV9交付大大减少了 与全身交付和实现相比，需要实现等量或更大的大脑翻译所需的矢量 相对于注射部位的高CNS翻译。因此，我们预测AAV9的IT交付合并 伴有th骨FUS将允许对大脑的基因疗法进行局灶性和广泛的靶向靶向，并成为一种 与年龄相关的神经退行性疾病的有效分娩方法。该赠款将发展使用 将FUS及IT注射作为AAV向量向大脑的有效输送方法，定义机制 对于此增强，请确定矢量帽和启动子使用情况，并在鼠标模型中测试此应用 tauopathy。如果我们成功了，则可以轻松地翻译这种方法来治疗神经退行性 疾病。