Intrathecal Gene Therapy Expressing IGF-1 for Amyotrophic Lateral Sclerosis

表达 IGF-1 的鞘内基因疗法治疗肌萎缩侧索硬化症

基本信息

批准号：
8719821
负责人：
NICHOLAS M BOULIS
金额：
$ 19.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719821
关键词：
Affect Age Amyotrophic Lateral Sclerosis Animal Model Animals Apoptotic Astrocytes Attenuated Binding Biological Preservation Bolus Infusion Cells Cessation of life Clinic Clinical Trials Data Denervation Dependovirus Diffusion Disease Disease Progression Disease model Dose Effectiveness Employee Strikes Equilibrium Exhibits Family suidae Fibrinogen Foundations Frequencies Future Genetic Heterogeneity Human Individual Injection of therapeutic agent Insulin-Like Growth Factor I Intrathecal Injections Intravenous Lead Longevity Measures Mediating Methods Microglia Modality Modeling Motor Motor Neurons Muscle Muscle denervation procedure Muscular Atrophy Nature Neurites Neuromuscular Diseases Neuromuscular Junction Neurons Onset of illness Patients Persons Procedures Rattus Recombinant Proteins Regimen Respiratory Failure Rodent Model Route Safety Serotyping Signal Transduction Site Spinal Cord Symptoms Techniques Testing Therapeutic Toxicology Translating Work base clinical application dosage effective therapy gene therapy grasp inflammatory marker loss of function motor function improvement muscle form nerve supply neuron loss pre-clinical public health relevance receptor research study response retrograde transport scale up transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disorder striking about 1 person in 40,000 each year. Individuals with ALS exhibit rapid loss of muscle control, muscle atrophy, and death due to respiratory failure. The cause of ALS is the progressive denervation of muscle by motor neurons. There is currently no cure for this disease, and the only approved therapy has a very modest effect on the disease progression. Clearly, there is a pressing need for more effective therapies. One possible route would be to use neuroprotective factors which, due to their general mode of action, may have utility in other neuromuscular disorders as well. Our long-term objective for this project is to develop gene therapy for ALS. Previous studies have investigated the use of neuroprotective factors. These molecules, such as insulin-like growth factor 1 (IGF-1) provide anti-apoptotic signals for motor neurons as well as promoting neurite outgrowth. These molecules seemed promising in animal studies. However, clinical trials demonstrated that scaling the dose to humans poses daunting challenges. A more effective approach might be to use gene therapy to allow the patients' own cells to produce the therapeutic factor. Several studies, including our own, have shown this approach has merit. However, these studies used techniques that have not scaled up well in larger animal models. Intraparenchymal injection into the spinal cord results in only localized transgene expression and thus would require an unreasonably large number of injections in humans. Retrograde transport in motor neurons of vector injected into muscle was also effective in a rodent model of ALS, but again would likely have limited clinical applicability due to the muscle mass that would need to be injected. In this proposal we will investigate efficacy of intrathecally administered gene therapy expressing IGF-1 in the SOD1-G93A rat model of ALS. In Specific Aim 1, we show that our gene therapy can promote motor neuron survival and protect the integrity of neuromuscular junctions. In addition we will show that this therapy attenuates the activation of astrocytes and microglia that helps contribute to th destruction of motor neurons. Furthermore, we will investigate the possibility that motor neurons can develop tolerance to elevated levels of IGF-1, a phenomenon that could limit the effectiveness of this therapy long-term. In Specific Aim 2, we will show that the improvements found in Aim 1 translate into improved motor function and increased life span. SOD1 rats will be evaluated using the grip strength, rotarod, and open field tests to evaluate several aspects of motor function. In addition, life span, age at disease onset, and the rate of disease progression will be measured to show efficacy. This study will provide the proof-of-principle data necessary to support future clinical trials of this approach.

描述（由申请人提供）：肌萎缩侧索硬化症 (ALS) 是一种毁灭性的神经肌肉疾病，每年约有四万人中就有 1 人罹患这种疾病。患有 ALS 的个体会迅速失去肌肉控制、肌肉萎缩，并因呼吸衰竭而死亡。 ALS 的病因是运动神经元对肌肉进行性去神经支配。目前尚无治愈这种疾病的方法，唯一批准的疗法对疾病进展的影响非常有限。显然，迫切需要更有效的治疗方法。一种可能的途径是使用神经保护因子，由于其一般作用模式，神经保护因子也可能对其他神经肌肉疾病有用。我们这个项目的长期目标是开发 ALS 的基因疗法。先前的研究已经调查了神经保护因子的使用。这些分子，例如胰岛素样生长因子 1 (IGF-1)，为运动神经元提供抗凋亡信号并促进神经突生长。这些分子在动物研究中似乎很有前景。然而，临床试验表明，扩大人体剂量面临着艰巨的挑战。更有效的方法可能是使用基因疗法让患者自身的细胞产生治疗因子。包括我们自己在内的多项研究表明这种方法具有优点。然而，这些研究使用的技术尚未在大型动物模型中很好地推广。脊髓实质内注射仅导致局部转基因表达，因此在人体中需要不合理地大量注射。注射到肌肉中的载体的运动神经元的逆行运输在 ALS 啮齿动物模型中也有效，但由于需要注射的肌肉质量，其临床适用性可能再次受到限制。在本提案中，我们将研究鞘内注射表达 IGF-1 的基因治疗在 ALS SOD1-G93A 大鼠模型中的疗效。在具体目标 1 中，我们表明我们的基因疗法可以促进运动神经元存活并保护神经肌肉接头的完整性。此外，我们将证明这种疗法会减弱星形胶质细胞和小胶质细胞的活化，从而有助于破坏运动神经元。此外，我们将研究运动神经元对 IGF-1 水平升高产生耐受性的可能性，这种现象可能会限制这种疗法的长期有效性。在具体目标 2 中，我们将展示目标 1 中发现的改进可以转化为运动功能的改善和寿命的延长。 SOD1 大鼠将使用握力、旋转棒和旷场测试进行评估，以评估运动功能的多个方面。此外，还将测量寿命、发病年龄和疾病进展速度以显示疗效。这项研究将提供支持该方法未来临床试验所需的原理验证数据。