Spinal muscular atrophy therapy using recombinant SMN proteins

使用重组 SMN 蛋白治疗脊髓性肌萎缩症

基本信息

批准号：
8771212
负责人：
RUI ZHAO
金额：
$ 19.38万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771212
关键词：
Amino Acids Animal Experiments Antibodies Biogenesis Blood flow Brain California Cell membrane Cells Cessation of life Charge Clinical Collaborations DNA Data Disease Early treatment Enzymes Escherichia coli Event Exons Fibroblasts Frequencies Galactosidase Genetic Genetic Transcription Grant Hereditary Disease Human Infant Mortality Intraperitoneal Injections Length Life Live Birth Marketing Molecular Motor Motor Neurons Mus Muscle Weakness Mutation Myocardial Infarction Neurodegenerative Disorders Nuclear Nucleotides Oligonucleotides Pathogenesis Patients Peptides Phase II Clinical Trials Phenotype Proteins RNA RNA Splicing Recombinant Proteins Recombinants Research Respiratory distress Risk SMN protein (spinal muscular atrophy)SMN1 gene SMN2 gene Severity of illness Small Nuclear Ribonucleoproteins Specificity Spinal Spinal Muscular Atrophy Spliced Genes System Testing Therapeutic Therapeutic Agents Therapeutic Uses Time Tissues Toxic effect Trans-Activators Transcript United States Universities Vaccines Weight cell type disorder prevention drug development exon skipping experience gene therapy immunogenicity improved in vivo infant death mRNA Precursor mouse model novel strategies protein expression protein kinase C-delta protein purification public health relevance small molecule survival motor neuron gene tat Protein therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a neurodegenerative disease of the motor neuron that is caused by deletion or mutation of the survival motor neuron gene (SMN1). SMN1 encodes the survival motor neuron (SMN) protein that is important for the biogenesis of small nuclear ribonucleoprotein particles that are important for pre-mRNA splicing, but the splicing target involved in SMA pathogenesis remains unclear. Humans contain a second and partially functional SMN2, which contains one nucleotide difference in exon 7 compared to SMN1, leading to the skipping of exon 7 in most SMN2 transcripts and truncated SMN proteins. Limited amount of functional full-length SMN protein is expressed from SMN2 but it typically cannot compensate for the loss of SMN1. The loss of SMN protein causes debilitating muscle weakness, respiratory distress, and death in severe cases. SMA occurs at a frequency of one in 6,000 to one in 10,000 live births and it is the leading genetic cause of infant mortality in the United States. There is currently no treatment or prevention of the disease, although a number of approaches have been extensively researched as potential therapeutics. These approaches include gene therapy to deliver the SMN1 gene, and splicing modulation of SMN2 using anti-sense oligo or small molecules to increase the expression of full-length SMN proteins. In this project, we propose a new approach to compensate for the loss of SMN using recombinant SMN protein conjugated to a cell penetrating peptide (CPP). CPP are short (10-30 amino acids in length) and highly positively charged peptides that can bring its covalently conjugated molecular cargos (including DNA, RNA, peptide, and protein) into almost all cell types. In this proposal, we will evaluate the possibility of using CPP-SMN conjugate for SMA therapy.

描述（申请人提供）：脊髓性肌萎缩症（SMA）是一种运动神经元的神经退行性疾病，由运动神经元存活基因（SMN1）的缺失或突变引起。 SMN1 编码运动神经元存活 (SMN) 蛋白，该蛋白对于小核核糖核蛋白颗粒的生物发生非常重要，而小核核糖核蛋白颗粒对于前 mRNA 剪接很重要，但参与 SMA 发病机制的剪接靶点仍不清楚。人类含有第二个且部分功能的 SMN2，与 SMN1 相比，其在外显子 7 中包含一处核苷酸差异，导致大多数 SMN2 转录物和截短的 SMN 蛋白中外显子 7 被跳过。 SMN2 表达有限量的功能性全长 SMN 蛋白，但它通常无法补偿 SMN1 的损失。 SMN 蛋白的缺失会导致肌肉无力、呼吸困难，严重时甚至导致死亡。 SMA 的发生频率为六千分之一到万分之一的活产儿，它是美国婴儿死亡的主要原因。目前尚无治疗方法或预防疾病，尽管许多方法作为潜在的治疗方法已被广泛研究。这些方法包括传递 SMN1 基因的基因治疗，以及使用反义寡核苷酸或小分子对 SMN2 进行剪接调节，以增加全长 SMN 蛋白的表达。在这个项目中，我们提出了一种使用与细胞穿透肽（CPP）缀合的重组 SMN 蛋白来补偿 SMN 损失的新方法。 CPP 是短肽（长度为 10-30 个氨基酸）且带高正电荷的肽，可以将其共价结合的分子货物（包括 DNA、RNA、肽和蛋白质）带入几乎所有细胞类型。在本提案中，我们将评估使用 CPP-SMN 结合物进行 SMA 治疗的可能性。