Delivery of a Myostatin Inhibitor by AAV Gene Therapy for Muscular Dystrophy

通过 AAV 基因疗法递送肌肉生长抑制素抑制剂治疗肌营养不良症

基本信息

批准号：
7644842
负责人：
Amanda Haidet-Phillips
金额：
$ 2.35万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-06-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644842
关键词：
Actins Adrenal Cortex Hormones Adverse effects Affect Amyotrophic Lateral Sclerosis Birth Cardiac Cataract Clinical Trials Complex Cytoskeletal Proteins Cytoskeleton Defect Delayed Puberty Dependency Dependovirus Disease Dose Duchenne muscular dystrophy Dystrophin Extracellular Matrix Fibrosis Follistatin Genes Germ Cells Heart failure Hemophilia B Hereditary Disease Hypertension Incidence Injection of therapeutic agent Intramuscular Knowledge Life Liver Longevity Mediating Medical Methods Morbidity - disease rate Muscle Muscle Weakness Muscular Dystrophies Mutation Myocardium Myopathy Natural regeneration Pathology Patients Play Portal vein structure Proteins Respiratory Muscles Respiratory Tract Infections Role Site Skeletal Muscle Steroids Systemic Therapy Teenagers Therapeutic Therapeutic Effect Thinking Virus Weight Gain Wheelchairs adeno-associated viral vector bone loss effective therapy gene therapy improved inhibitor/antagonist male mdx mouse mortality mouse model muscle regeneration muscle strength myostatin pre-clinical repaired skeletal standard care success

项目摘要

DESCRIPTION (provided by applicant): Duchenne's muscular dystrophy (DMD) affects 1 in 3500 live male births. DMD is characterized byprogressive muscle weakness and degeneration often leading to wheelchair dependency in the early teens. Mortality is usually a result of respiratory infection complicated by cardiac failure and most often occurs in late teens or early twenties. It is disappointing that despite tremendous medical advances, the lifespan of the DMD patient has not been significantly improved. There is no known cure and few new successful therapies have been added to the standard treatment repertoire. Overall, the high incidence (1/3500) of DMD, early morbidity and mortality, and lack of effective treatments provide urgent reasons to find other therapies. With the realization that structural defects in DMD will be very difficult to repair given that the defective protein dystrophin is normally part of a large and complex structural network, new thoughts have emerged which focus on muscle regeneration and reduced fibrosis. These 'muscle booster genes' encode for proteins that promote survival and regeneration of the compromised muscles. Myostatin inhibitors in particular have shown great promise and early pre-clinical signs for success. Additionally, adeno-associated virus (AAV)-mediated gene therapy has demonstrated potential for treating a number of genetic disorders. However, without a means of systemic delivery of AAV, the therapeutic effects of gene therapy will never reach cardiac and respiratory muscles needed to avoid problems that are the major causes for mortality in MD patients. Therefore, we propose to determine the optimal delivery method of an AAV vector encoding a secreted myostatin inhibitor by comparing intramuscular versus portal vein delivery in a mouse model of DMD, the dystrophin deficient mdx mouse. By optimizing a delivery method of a secreted myostatin inhibitor either to muscle or liver, we may ultimately gain a systemic therapy suitable for long-term therapy in DMD. Our Specific Aims are: 1. To determine whether intramuscular or portal vein delivery of AAV1 expressing the secreted myostatin inhibitor, follistatin, enhances muscle strength and coordination in the mdx mouse model of DMD. 2. To determine whether intramuscular or portal vein delivery of AAV1 expressing the secreted myostatin inhibitor, follistatin, can reverse or delay the dystrophic muscle pathology in the mdx mouse.

描述（由申请人提供）：每 3500 名活产男婴中就有 1 人患有杜氏肌营养不良症 (DMD)。 DMD 的特点是进行性肌肉无力和退化，通常导致青少年早期依赖轮椅。死亡通常是呼吸道感染并发心力衰竭的结果，最常发生在十几岁或二十岁出头。令人失望的是，尽管医学取得了巨大的进步，DMD患者的寿命却没有得到显着改善。目前还没有已知的治疗方法，并且标准治疗方案中添加的新的成功疗法也很少。总体而言，DMD 的高发病率（1/3500）、早期发病率和死亡率以及缺乏有效的治疗方法为寻找其他治疗方法提供了紧迫的理由。由于有缺陷的肌营养不良蛋白通常是大型复杂结构网络的一部分，DMD 的结构缺陷将很难修复，因此出现了关注肌肉再生和减少纤维化的新想法。这些“肌肉增强基因”编码的蛋白质可以促进受损肌肉的存活和再生。肌生长抑制素抑制剂尤其显示出巨大的前景和成功的早期临床前迹象。此外，腺相关病毒（AAV）介导的基因治疗已被证明具有治疗多种遗传性疾病的潜力。然而，如果没有 AAV 的全身递送方法，基因治疗的治疗效果将永远无法到达避免 MD 患者死亡主要原因所需的心脏和呼吸肌。因此，我们建议通过比较 DMD 小鼠模型（肌营养不良蛋白缺陷型 mdx 小鼠）的肌内注射与门静脉注射，确定编码分泌型肌生长抑制素抑制剂的 AAV 载体的最佳递送方法。通过优化分泌型肌生长抑制素抑制剂向肌肉或肝脏的递送方法，我们最终可能获得适合 DMD 长期治疗的全身疗法。我们的具体目标是： 1. 确定肌内或门静脉递送表达分泌型肌生长抑制素抑制剂（卵泡抑素）的 AAV1 是否可以增强 DMD 的 mdx 小鼠模型的肌肉力量和协调性。 2. 确定肌内或门静脉递送表达分泌型肌生长抑制素抑制剂（卵泡抑素）的 AAV1 是否可以逆转或延缓 mdx 小鼠的营养不良性肌肉病理。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Could gene therapy be the future for muscular dystrophy?

基因疗法会成为肌营养不良症的未来吗？

DOI：
10.2217/thy.10.14
发表时间：
2010
期刊：
Therapy (London, England : 2004)
影响因子：
0
作者：
Haidet,AmandaM;Mendell,JerryR;Kaspar,BrianK
通讯作者：
Kaspar,BrianK

Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease.

DOI：
10.1002/mus.21244
发表时间：
2009-03
期刊：
MUSCLE & NERVE
影响因子：
3.4
作者：
Rodino-Klapac, Louise R.;Haidet, Amanda M.;Kota, Janaiah;Handy, Chalonda;Kaspar, Brian K.;Mendell, Jerry R.
通讯作者：
Mendell, Jerry R.

Astrocytes from familial and sporadic ALS patients are toxic to motor neurons.

DOI：
10.1038/nbt.1957
发表时间：
2011-08-10
期刊：
Nature biotechnology
影响因子：
46.9
作者：
通讯作者：

Follistatin gene delivery enhances muscle growth and strength in nonhuman primates.

DOI：
10.1126/scitranslmed.3000112
发表时间：
2009-11-11
期刊：
Science translational medicine
影响因子：
17.1
作者：
Kota J;Handy CR;Haidet AM;Montgomery CL;Eagle A;Rodino-Klapac LR;Tucker D;Shilling CJ;Therlfall WR;Walker CM;Weisbrode SE;Janssen PM;Clark KR;Sahenk Z;Mendell JR;Kaspar BK
通讯作者：
Kaspar BK