Adeno-associated Viral Vector Modification for Targeted Motor Neuron Therapy

用于靶向运动神经元治疗的腺相关病毒载体修饰

• 批准号: 7892423
• 负责人: NICHOLAS M BOULIS
• 金额: $ 22.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892423
• 关键词: Adverse effects; Affect; Affinity; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Binding; Blood - brain barrier anatomy; Capsid; Capsid Proteins; Cell Death; Cell membrane; Cessation of life; Characteristics; Clinical Treatment; Clinical Trials; Computer Simulation; Data; Development; Disease; Engineering; Epitopes; Exhibits; Foundations; Gene Delivery; Gene Expression; Generations; Genes; Grant; Growth Factor; Growth Factor Gene; Half-Life; Hindlimb; Human; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Intra-Arterial Injections; Intramuscular; Intramuscular Injections; Intrathecal Injections; Lead; Mediating; Modeling; Modification; Molecular; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Mutation; Nervous system structure; Neurodegenerative Disorders; Neurons; Parents; Pathway interactions; Peptides; Peripheral Nerves; Phase I Clinical Trials; Presynaptic Terminals; Primates; Process; Production; Progressive Muscular Atrophy; Proteins; Rattus; Research Personnel; Route; Safety; Serotyping; Site-Directed Mutagenesis; Skeletal Muscle; Source; Specificity; Spinal Cord; Testing; Tetanus Helper Peptide; Therapeutic; Translating; Tropism; Variant; Viral; Viral Vector; Virus; adeno-associated viral vector; base; disability; gene therapy; improved; in vivo; motor neuron degeneration; mouse model; mutant; neural growth; neuroprotection; novel; pre-clinical; prevent; public health relevance; respiratory; retrograde transport; therapeutic development; therapeutic gene; therapeutic protein; uptake; vector

DESCRIPTION (provided by applicant): Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA), are progressive neurodegenerative disorders that share the common characteristic of upper and/or lower motor neuron (MN) degeneration. Although the molecular mechanisms underlying MND are not entirely clear, all forms ultimately lead to apoptotic motor neuron death. Therapeutic strategies for MND, using trophic factors, or anti-apoptotic proteins can confer MN protection regardless of the specific mechanism of injury. Currently, gene therapy is one of the most promising candidates to deliver these treatments in MND, using lentiviral and adeno-associated viral (AAV) vectors. Because of the attractive safety profile of AAV vectors a variety of clinical trials are ongoing or planned for application to neurodegenerative diseases including ALS. Despite their appealing characteristics, AAV vectors have high affinity for skeletal muscle, as well as limited tropism for axon terminals, impeding MN gene delivery after IM injection. These limitations halted the aggressive development of a clinical trial for the treatment of ALS through intramuscular AAV.IGF-I injection. To overcome this barrier, we have modified the vector's capsid through the insertion of a novel peptide (Tet1) with high MN affinity and retrograde transport, increasing AAV mediated MN gene delivery. The present grant seeks support to identify the optimal targeted AAV vector for enhanced MN gene delivery, and demonstrate improved survival in the rat model of ALS compared to the earlier generation vector. Substantially improved retrograde delivery will prompt a return to the aggressive development of a clinical trial for ALS gene therapy. Our application will attempt to demonstrate that: 1. Capsid Mutation of the AAV Cap gene, incorporating novel neuronal binding peptides into the virus' coat, can increase the efficiency and specificity of MN gene delivery. 2. Targeted AAV-mediated IGF-I gene expression will protect MNs in SOD1 rats. 3. Peptide insertion may enhance neuronal delivery following alternative delivery routes, such as intra-arterial and intrathecal injections. PUBLIC HEALTH RELEVANCE: Death and disability in Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS), result from death of cells in the nervous system called motor neurons (MN). In the present application, we will engineer viruses for safe and enhanced delivery of therapeutic genes to motor neurons. These viruses will be capable of delivering genes to the spinal cord after simple muscle injection, providing a safe approach to gene therapy for ALS.

描述（由申请人提供）：运动神经元疾病（MND），如肌萎缩性侧索硬化症（ALS）和脊髓性肌萎缩症（SMA），是具有上和/或下运动神经元（MN）变性共同特征的进行性神经退行性疾病。虽然MND的分子机制还不完全清楚，但所有形式最终都会导致运动神经元凋亡。无论损伤的具体机制如何，使用营养因子或抗凋亡蛋白的MND治疗策略都可以提供MN保护。目前，基因治疗是最有前途的候选人之一，提供这些治疗MND，使用慢病毒和腺相关病毒（AAV）载体。由于AAV载体的有吸引力的安全性特征，正在进行或计划进行各种临床试验以应用于神经退行性疾病，包括ALS。尽管它们具有吸引人的特征，但AAV载体对骨骼肌具有高亲和力，以及对轴突终末的有限向性，阻碍了IM注射后的MN基因递送。这些限制阻止了通过肌内AAV.IGF-I注射治疗ALS的临床试验的积极发展。为了克服这一障碍，我们通过插入具有高MN亲和力和逆行转运的新型肽（Tet 1）来修饰载体的衣壳，从而增加AAV介导的MN基因递送。目前的资助寻求支持，以确定增强MN基因递送的最佳靶向AAV载体，并证明与前一代载体相比，ALS大鼠模型的存活率提高。实质性改进的逆行递送将促使ALS基因治疗临床试验的积极发展。我们的应用程序将试图证明：1。衣壳突变的AAV Cap基因，纳入新的神经元结合肽到病毒的外壳，可以提高效率和特异性的MN基因输送。2.靶向腺相关病毒介导的IGF-I基因表达将保护SOD 1大鼠的MN。3.肽插入可以增强替代递送途径（例如动脉内和鞘内注射）之后的神经元递送。 公共卫生关系：运动神经元疾病（MND），如肌萎缩性侧索硬化症（ALS）的死亡和残疾是由神经系统中称为运动神经元（MN）的细胞死亡引起的。在本申请中，我们将工程化病毒以安全和增强治疗基因向运动神经元的递送。这些病毒将能够在简单的肌肉注射后将基因传递到脊髓，为ALS的基因治疗提供了一种安全的方法。