Gene delivery to muscle and nerve for laminin-alpha2-deficient MD (MDC1A)

将基因传递至肌肉和神经以治疗层粘连蛋白 α2 缺陷型 MD (MDC1A)

• 批准号: 8503991
• 负责人: Xiao Xiao
• 金额: $ 33.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503991
• 关键词: Address; Adverse effects; Affect; Affinity; Agrin; Binding; Biochemical; Blood; Blood - brain barrier anatomy; Brain; CMV promoter; Cardiac; Cell membrane; Cessation of life; Child; Codon Nucleotides; Complementary DNA; Disease; Dose; Dystroglycan; Engineering; Extracellular Matrix; Gene Delivery; Gene Expression; Gene Transfer; Genes; Genetic; Goals; Growth; Hand; Hindlimb; Human; Immune response; Integrins; Knock-out; Laminin; Length; Liver; Longevity; MDC1A; Mannitol; Membrane; Merosin; Methods; MicroRNAs; Monitor; Monkeys; Motor; Mus; Muscle; Muscle Cells; Myocardium; Nerve; Neuraxis; Neuromuscular Diseases; Paralysed; Pathology; Patients; Peptides; Peripheral Nerves; Physiological; Property; Protein Isoforms; Rabies virus; Reporting; Research; Safety; Serotyping; Specificity; Spinal Cord; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Treatment Efficacy; Vascular Endothelial Growth Factors; adeno-associated viral vector; cognitive function; congenital muscular dystrophy; functional improvement; gene therapy; improved; monomer; mouse model; natural hypothermia; nervous system disorder; neurological pathology; neurotropic; novel; particle; postnatal; premature; public health relevance; safety study; success; therapeutic gene; tool; transgene expression; yeast two hybrid system

DESCRIPTION (provided by applicant): Congenital muscular dystrophy (CMD) is a class of currently untreatable, severe genetic neuromuscular disorders affecting muscle as well as the central nervous system (CNS). The laminin-¿2(merosin)-deficient congenital muscular dystrophy (MDC1A) is the most common of them, afflicts 4 in 500,000 children and causes premature death. The purpose of this proposal is to develop an efficient and non-invasive gene delivery method to cross the blood brain barrier (BBB) to the CNS, in addition to the muscle and heart. The method will be tested in a laminin ¿2-knockout dyw/dyw mouse model with a mini-agrin gene to replace the lost functions of laminin ¿2. Previously we showed that systemic AAV1-mini-agrin delivery greatly improved muscle pathology and extended their lifespan but it failed to deliver to the CNS for improvement of neurological pathology. Recently we found that transient hypothermia greatly enhances AAV delivery into the spinal cord and brain. We have also engineered new chimeric mini-agrin genes with broadened binding substrates and higher affinities. While further optimizing the technology, we propose to use the new enabling tools to test our general hypothesis that revamped mini-agrin gene delivery to muscle, heart and CNS will provide: 1) better and broader therapeutic benefits for muscle and nerve pathologies; and 2) greater improvement in physiological functions and lifespan of the dyw/dyw mouse model. The success of this research plan could be potentially translatable to MDC1A patients and to other neuromuscular diseases as well.

描述（由应用提供）：先天性肌肉营养不良（CMD）是一类目前不可治疗的，严重的，严重的遗传神经肌肉疾病，影响肌肉以及中枢神经系统（CNS）。层粘连蛋白2（Merosin） - 缺陷先天性肌肉营养不良（MDC1A）是最常见的，在500,000名儿童中折磨了4个，并造成早死亡。该建议的目的是开发一种有效且非侵入性的基因递送方法，除了肌肉和心脏外，还将血脑屏障（BBB）越过CNS。该方法将在粘贴蛋白»2-KNOCKOUT DYW/DYW Mouse模型中进行测试，以取代层粘连蛋白的丢失功能。2。我们表明，有系统性的AAV1-Mini-Gagrin可以极大地改善肌肉病理学的肌肉病理学并延长了其寿命，但未能延长其为改善神经学病理学的肌肉病理学。最近，我们发现瞬时体温过低会大大增强AAV输送到脊髓和大脑中。我们还设计了具有扩展结合基板和更高亲和力的新型嵌合迷你基因基因。在进一步优化该技术的同时，我们建议使用新的启示工具来测试我们的一般假设，即对肌肉，心脏和中枢神经系统的改造为肌肉，心脏和CNS提供：1）对肌肉和神经病理的更好，更广泛的治疗益处； 2）DYW/DYW小鼠模型的物理功能和寿命的改善。该研究计划的成功可能可以转化为MDC1A患者以及其他神经肌肉疾病。