Delivery of therapeutic genes in motor neuron disease

描述(申请人提供)：脊髓性肌萎缩症(SMA)和肌萎缩侧索硬化症(ALS)是致命的运动神经元疾病，目前还没有重要的治疗方法。通过血脑屏障(BBB)将治疗剂输送到中枢神经系统是一个严重的问题，阻碍了治疗SMA和ALS等神经退行性疾病的有效开发。在这里，我们建议开发一种简单的血管传递，以跨血脑屏障转导基因，并对神经疾病的治疗产生影响。我们已经发现了腺相关病毒(血清9型)穿越血脑屏障的独特能力，并有效地靶向大脑和脊髓内的运动神经元和星形胶质细胞。在这里，我们希望在小鼠身上扩展这些研究，并将它们转化为非人类灵长类动物，以开发有前景的运动神经元疾病的治疗方法。在这里，我们建议(1)优化小鼠模型中SMA的纠正和ALS的治疗，(2)为运动神经元和星形胶质细胞在非人灵长类动物中靶向的血管传递途径，以及(3)确定在突变的SOD1小鼠模型中识别的ALS靶点是否在人类散发性和家族性SOD1ALS模型中起作用。我们已经组建了一支拥有研究SMA和ALS的所有关键专业知识的调查团队。这项建议包括的研究不仅将进一步了解运动神经元疾病的生物学机制，还将导致开发一种血管输送疗法的技术，该技术将对许多神经疾病产生广泛影响。 与公共健康相关：这种给药系统将彻底改变所有神经疾病的治疗方法。我们将特别关注两种主要的运动神经元疾病，脊髓肌萎缩症(SMA)和肌萎缩侧索硬化症(ALS)。SMN在SMA中的交付将带来重大好处。

DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are fatal motor neuron disorders for which no significant treatments currently exist. Delivery of a therapeutic agent across the blood brain barrier (BBB) to the central nervous system is a significant problem that prevents the effective development of therapies to treat neurodegenerative diseases such as SMA and ALS. Here we propose to develop a simple vascular delivery to transduce genes across the BBB and have an impact on treatment of neurological disorders. We have discovered the unique capacity for the adeno-associated virus (serotype 9) to traverse the BBB and to efficiently target motor neurons and astrocytes within the brain and spinal cord. Here we wish to expand on these studies in mice and to translate them into the non-human primate in order to develop promising therapies for motor neuron disease. Here we propose (1) to optimize the correction of SMA and treatment of ALS in mouse models, (2) to develop a vascular delivery route for motor neuron and astrocytes targeting in the non-human primate and (3) to determine if ALS targets identified in mutant SOD1 mouse models function in human sporadic and familial SOD1 ALS models. We have assembled a team of investigators with all the critical expertise for the study of both SMA and ALS. This proposal includes studies that will not only further the understanding of the biological mechanism of motor neuron disease, but will also lead to the development of a technique for vascular delivery of therapeutics that will have widespread impact for many neurological disorders. PUBLIC HEALTH RELEVANCE: This delivery system will revolutionize therapies for all neurological disorders. We will specifically focus on the two major motor neuron disorders, Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS). The delivery of SMN in SMA will have a major benefit.