Delivery of therapeutic genes in motor neuron disease

描述（由申请方提供）：脊髓性肌萎缩症（SMA）和肌萎缩性侧索硬化症（ALS）是目前尚无显著治疗方法的致死性运动神经元疾病。将治疗剂穿过血脑屏障（BBB）递送至中枢神经系统是阻碍治疗神经退行性疾病如SMA和ALS的疗法的有效开发的重要问题。在这里，我们建议开发一种简单的血管递送到跨越BBB的E12基因，并对神经系统疾病的治疗产生影响。我们已经发现腺相关病毒（血清型9）穿越血脑屏障并有效靶向脑和脊髓内的运动神经元和星形胶质细胞的独特能力。在这里，我们希望在小鼠中扩展这些研究，并将其转化为非人类灵长类动物，以开发有希望的运动神经元疾病治疗方法。在这里，我们提出（1）优化小鼠模型中SMA的校正和ALS的治疗，（2）开发非人灵长类动物中运动神经元和星形胶质细胞靶向的血管递送途径，以及（3）确定突变型SOD1小鼠模型中鉴定的ALS靶点是否在人散发性和家族性SOD1 ALS模型中发挥作用。我们已经组建了一个研究团队，拥有SMA和ALS研究的所有关键专业知识。该提案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，而且还将导致开发一种用于血管递送治疗剂的技术，该技术将对许多神经系统疾病产生广泛影响。 公共卫生相关性：这种输送系统将彻底改变所有神经系统疾病的治疗方法。我们将特别关注两种主要的运动神经元疾病，脊髓性肌萎缩症（SMA）和肌萎缩性侧索硬化症（ALS）。在SMA中递送SMN将具有重大益处。

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.