Antisense oligonucleotide suppression of Duchenne Muscular Dystrophy

杜氏肌营养不良症的反义寡核苷酸抑制

• 批准号: 7210764
• 负责人: STEPHEN D WILTON
• 金额: $ 14.21万
• 依托单位: UNIVERSITY OF WESTERN AUSTRALIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210764
• 关键词: Affect; Animal Model; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Architecture; Becker Muscular Dystrophy; Binding; Biological Assay; Cells; Chemistry; Clinical; Complex; Condition; Disease; Duchenne muscular dystrophy; Dystrophin; Environment; Exons; Family; Fiber; Gene Mutation; Genes; Genetic; Genomics; Goals; Heterogeneous Nuclear RNA; Human; Immune response; In Vitro; Interphase Cell; Intervention; Intramuscular; Lesion; Measurable; Modification; Molecular; Muscle; Muscle Cells; Muscular Dystrophies; Mutation; Myocardium; Nonsense Mutation; Numbers; Oral; Pathology; Patients; Phenotype; Physiological; Physiology; Process; Protein Isoforms; Proteins; Quality of life; RNA Splicing; Reading Frames; Relative (related person); Replacement Therapy; Research Personnel; Route; Severities; Severity of illness; Site; Skeletal system; Therapeutic; Tissues; Transcript; Treatment Protocols; base; boys; design; disease-causing mutation; gene replacement; improved; in vivo; intraperitoneal; mRNA Precursor; mdx mouse; programs; promoter; size; subcutaneous; uptake

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop an antisense oligonucleotide (AO) therapy for Duchenne muscular dystrophy (DMD). Antisense oligonucleotides (AOs) can be used to reduce the severity of DMD by removing specific exons during pre-mRNA splicing, to either by-pass nonsense mutations or restore the reading frame around dystrophin genomic deletions. As a result of the treatment, dystrophin expression would be restored in dystrophic tissue and DMD patients would theoretically manifest only the milder phenotype of Becker Muscular Dystrophy (BMD). This project will explore the design and delivery of AOs to minimize the consequences of disease-causing dystrophin gene mutations. (1) Animal models of muscular dystrophy will be used to develop treatment regimens and assess therapeutic benefits in vivo. (2) AOs will be designed to target the most amenable splicing motifs at relevant exons in the human dystrophin gene transcript and will be evaluated in cultured human muscle cells. Although this approach cannot permanently correct the primary genetic lesion, we propose that repeated administration, preferably through systemic delivery, should be feasible. AO chemistries or modifications to increase stability and/or uptake, optimized for in vivo induction of exon skipping, will be developed and evaluated. Only periodic administration of AOs should be required to maintain therapeutic levels of induced dystrophin in dystrophic muscle. DMD is a serious disorder for which there is no effective treatment. AOs will not cure this devastating condition, however, AO-based splicing intervention has the potential to reduce the severity of DMD so that treated boys should be able to produce some functional dystrophin. This would be expected to moderate the severity of DMD and improve the quality of life for patients and their families.

描述（由申请人提供）：本项目的最终目标是开发用于Duchenne型肌营养不良症（DMD）的反义寡核苷酸（AO）疗法。反义寡核苷酸（AO）可用于通过在前mRNA剪接期间去除特定外显子来降低DMD的严重性，以绕过无义突变或恢复肌营养不良蛋白基因组缺失周围的阅读框。作为治疗的结果，肌营养不良蛋白的表达将在营养不良组织中恢复，并且DMD患者理论上将仅表现出贝克肌营养不良症（BMD）的较温和表型。 该项目将探索AO的设计和交付，以最大限度地减少导致疾病的肌营养不良蛋白基因突变的后果。(1)肌营养不良症的动物模型将用于开发治疗方案和评估体内治疗益处。(2)AO将被设计为靶向人肌营养不良蛋白基因转录物中相关外显子处最易受影响的剪接基序，并将在培养的人肌肉细胞中进行评价。 虽然这种方法不能永久纠正原发性遗传病变，我们建议重复给药，最好是通过全身给药，应该是可行的。将开发和评价AO化学或修饰以增加稳定性和/或摄取，优化用于外显子跳跃的体内诱导。应仅需要定期施用AO以维持营养不良肌肉中诱导的肌营养不良蛋白的治疗水平。 DMD是一种严重的疾病，没有有效的治疗方法。AO不会治愈这种毁灭性的疾病，但是，基于AO的剪接干预有可能降低DMD的严重程度，因此治疗的男孩应该能够产生一些功能性肌营养不良蛋白。这有望减轻DMD的严重程度，改善患者及其家人的生活质量。