Whole body single AAV microgene therapy in canine DMD

犬 DMD 全身单一 AAV 微基因治疗

基本信息

批准号：
9751657
负责人：
Dongsheng Duan
金额：
$ 60.03万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751657
关键词：
Address Adult Affect Animal Model Attenuated Autopsy Becker Muscular Dystrophy Binding Biological Assay Biology Biopsy Blood flow Body Weight Canis familiaris Chronic Clinical Clinical Trials Code Complementary DNA Data Dependovirus Disease Dose Duchenne muscular dystrophy Dystrophin Echocardiography Electrocardiogram Engineering Extensor Fibrosis Forelimb Foundations Future Gene Transduction Agent Gene Transfer Genes Genome Goals Heart Hindlimb Histology Human Immune Individual Inflammation Injections Intramuscular Injections Knowledge Laboratories Lead Length Life Light Limb structure Magnetic Resonance Imaging Mammals Methods Modeling Monitor Mus Muscle Muscular Atrophy Muscular Dystrophies Mutation Myopathy Patients Performance Phenotype Physiological Preparation Proteins Protocols documentation Quality of life Regional Disease Reporter Genes Research Personnel Safety Skeletal Muscle Systemic Therapy Testing Time Toxic effect Translations Treatment Efficacy Tumor-infiltrating immune cells Viral Vector Wasting Syndrome Wheelchairs animal data base disease-causing mutation dosage gait examination gene replacement therapy gene therapy immunogenic immunoreaction improved intravenous injection micro-dystrophin mouse model non-invasive monitor novel particle prototype public health relevance response systemic intervention vector

项目摘要

DESCRIPTION (provided by applicant) Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency. Gene replacement therapy holds great promise to treat DMD. Adeno-associated virus (AAV) is the leading viral vector for muscle gene therapy. However AAV has a small packaging capacity (~ 5-kb) and it cannot carry the full-length dystrophin cDNA (~12-kb). A microgene is a super-small synthetic dystrophin gene. It contains one-third of the full-length dystrophin coding sequence. Studies from many laboratories suggest that micro-dystrophin can effectively ameliorate muscle disease in dystrophin-deficient mice. Unfortunately, translation to large mammals has so far not been very successful. We recently engineered a new ∆R2-15/∆R18-19/∆R20-23/∆C microgene (abbreviated as ∆R2 µDys) and tested it adult dystrophin-null dogs by single muscle injection using Y731F AAV-9. Two months later, we observed dramatic reduction of inflammation and fibrosis. Importantly, eccentric contraction-induced damage, a physiological hallmark of DMD, was significantly alleviated. Our study demonstrates for the first time that microdystrophin can treat dystrophinopathy in muscles of large mammals. Our results also suggest that the newly developed Y731F AAV-9 ∆R2 µDys vector may hold great translational potential. The overarching goal of this proposal is to address key questions related to future clinical translatio. Specifically, we will pursue two aims including (1) to test the hypothesis that regional intramuscular injection can lead to persistent protection in adult dystrophic dogs. This set of studies will allow us to evaluate the feasibility of life-quality improving therapy in late-stage wheelchair-bound patients in the future; and (2) to test the hypothesis that a single intravenous injection can lead to bodywide amelioration in young dystrophic dogs. DMD affects all muscles in the body. This set of studies will allow us to determine whether systemic intervention can radically change the disease course in affected individuals. Taking together, our studies will break through major barriers in the field and provide the much-needed large animal data to guide human trials in the future.

描述（由申请人提供）杜氏肌营养不良 (DMD) 是由肌营养不良蛋白缺乏引起的，腺相关病毒 (AAV) 是肌肉基因治疗的主要病毒载体，但 AAV 的包装能力较小（~ 5-）。 kb），并且不能携带全长肌营养不良蛋白 cDNA（~12-kb）。微基因是一种超小的合成肌营养不良蛋白基因，它包含全长肌营养不良蛋白编码序列的三分之一。许多实验室的研究表明，微型肌营养不良蛋白可以有效改善肌营养不良蛋白缺陷小鼠的肌肉疾病，不幸的是，迄今为止，我们最近设计了一种新的 ΔR2-15/ΔR18-19/Δ 。 R20-23/ΔC 微基因（缩写为 ΔR2 µDys）并通过以下方法对成年抗肌营养不良蛋白缺失狗进行了测试两个月后，我们观察到使用 Y731F AAV-9 进行单次肌肉注射，炎症和纤维化显着减少，这是 DMD 的一个生理标志，我们的研究首次证明，微肌营养不良蛋白可以显着减轻。我们的结果还表明，新开发的 Y731F AAV-9 ΔR2 µDys 载体可能具有巨大的转化潜力。该提案的目的是解决与未来临床转化相关的关键问题，具体而言，我们将追求两个目标，包括（1）测试区域肌肉注射可以对成年营养不良犬产生持久保护的假设。评估未来晚期坐轮椅患者生活质量改善治疗的可行性；(2) 检验单次静脉注射可导致年轻营养不良犬全身改善的假设。身体。这一系列研究将使我们能够确定系统干预是否可以从根本上改变受影响个体的疾病进程。总之，我们的研究将突破该领域的主要障碍，并提供急需的大动物数据来指导人体试验。未来。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Dystrophin R16/17-syntrophin PDZ fusion protein restores sarcolemmal nNOSμ.

肌营养不良蛋白 R16/17-肌营养不良蛋白 PDZ 融合蛋白恢复肌膜 nNOSμ。

DOI：
发表时间：
2018
期刊：
影响因子：
4.9
作者：
Patel, Aman;Zhao, Junling;Yue, Yongping;Zhang, Keqing;Duan, Dongsheng;Lai, Yi
通讯作者：
Lai, Yi

Night Activity Reduction is a Signature Physiological Biomarker for Duchenne Muscular Dystrophy Dogs.

夜间活动减少是杜氏肌营养不良症犬的标志性生理生物标志物。

DOI：
发表时间：
2015
期刊：
影响因子：
0
作者：
Hakim, Chady H;Peters, Austin A;Feng, Feng;Yao, Gang;Duan, Dongsheng
通讯作者：
Duan, Dongsheng

Micro-Dystrophin Gene Therapy Goes Systemic in Duchenne Muscular Dystrophy Patients.

微肌营养不良蛋白基因治疗在杜氏肌营养不良症患者中进行全身治疗。

DOI：
发表时间：
2018-07
期刊：
影响因子：
4.2
作者：
Duan; Dongsheng
通讯作者：
Dongsheng

High-resolution 3D tractography of fibrous tissue based on polarization-sensitive optical coherence tomography.

基于偏振敏感光学相干断层扫描的纤维组织高分辨率 3D 纤维束成像。

DOI：
发表时间：
2020-02
期刊：
影响因子：
0
作者：
Yao, Gang;Duan, Dongsheng
通讯作者：
Duan, Dongsheng

Microdystrophin Therapy Rescues Impaired Na Currents in Cardiac Purkinje Fibers From Dystrophin-Deficient Mdx Mice.

微肌营养不良蛋白疗法可挽救肌营养不良蛋白缺陷 Mdx 小鼠心脏浦肯野纤维中受损的 Na 电流。

DOI：
发表时间：
2022-08
期刊：
影响因子：
0
作者：
Ebner, Janine;Pan, Xiufang;Yue, Yongping;Sideromenos, Spyridon;Marksteiner, Jessica;Koenig, Xaver;Hilber, Karlheinz;Duan, Dongsheng
通讯作者：
Duan, Dongsheng