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Preclinical models, biomarkers, and therapy for myotonic dystrophy type 1

1 型强直性肌营养不良的临床前模型、生物标志物和治疗

基本信息

批准号：
10480097
负责人：
MAURICE SCOTT SWANSON
金额：
$ 49.37万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480097
关键词：
3&apos Untranslated Regions Address Adult Affect Alleles Animal Model Antisense Oligonucleotides Binding Biological Markers C9ORF72 CRISPR/Cas technology CUG repeat Coupled Cyclin-Dependent Kinases DNA Polymerase II DNA-Directed RNA Polymerase Defect Development Disease Drug Approval Event Exercise Exons Experimental Models Family Fragile X Syndrome Generations Genes Genetic Transcription Genome Goals Health Hereditary Disease Hexoses Histopathology Human In Vitro Insulin Knock-in Knock-in Mouse Length Ligands Link Mediating Messenger RNA Methods MicroRNAs Microsatellite Repeats Modeling Modification Molecular Mus Muscle Muscular Dystrophies Mutation Myocardium Myotonia Myotonic Dystrophy Myotonic dystrophy type 1 Neuromuscular Diseases Outcome Measure Pathogenesis Pathogenicity Pathway interactions Patient observation Patients Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Pre-Clinical Model Program Development Proteins RNA RNA Processing RNA Splicing RNA-Binding Proteins Recovery of Function Regulation Research Residual state Safety Series Skeletal Muscle Smooth Muscle Testing Therapeutic Therapeutic Intervention Toxic effect Transcription Elongation Translations Tremor/Ataxia Syndrome Untranslated RNA analog base biomarker development combinatorial design drug development effective therapy frontotemporal lobar dementia-amyotrophic lateral sclerosis functional disability improved in vivo inhibitor knock-down loss of function mRNA Precursor mouse model muscular structure mutant novel preclinical study repaired small molecule targeted treatment therapeutic development therapeutic target therapeutically effective therapy development tool transcriptome transcriptome sequencing treatment response

项目摘要

Myotonic dystrophy type 1 (DM1), which is caused by CTG expansions (CTGexp) in the 3' untranslated region of the DMPK gene, has been used as a model for RNA-mediated disease mechanisms associated with other microsatellite expansion diseases, including fragile X tremor/ataxia syndrome (FXTAS) and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). In DM1, transcription of the CTGexp mutation results in CUGexp RNAs that alter the developmental regulation of pre-mRNA processing and mRNA localization events mediated by the MBNL and CELF families of RNA binding proteins. However, additional cellular pathways, such as miRNA processing and repeat-associated non-AUG translation, have also been implicated in DM1 pathogenesis. Most importantly, no effective therapies exist to treat this neuromuscular disease. To address these deficiencies, this project is designed to generate more informative mouse experimental models for DM1 to elucidate the relative contribution of each of the proposed pathomechanisms and qualify RNA splicing defects as responsive biomarkers of therapeutic response with the goal of developing effective therapeutic approaches to decrease the toxic burden of CUGexp RNAs. Aim 1 builds upon our recent development of Dmpk CTGexp knockin mice generated using a combination of rolling circle amplification to generate large repeats in vitro and CRISPR/Cas9-mediated genome modification. Using an allelic series of increasing CTG repeat lengths that represent the late-onset to congenital spectrum of the DM1 pathogenic range, we will determine CTG length-dependent effects on skleletal and heart muscle structure/function, RNA processing/localization/turnover and RAN translation. Transcriptome analysis will be pursued further in Aim 2, which is based upon our prior observations that patient functional impairment corresponds to RNA splicing defects and MBNL loss of function, to determine if splicing defects qualify as effective biomarkers that are responsive to CUGexp levels, MBNL activity and therapeutic intervention. In Aim 3, we will broaden this therapeutic scope and evaluate multiple strategies, including antisense oligonucleotide (ASO)-mediated CUGexp knockdown and small molecule approaches to inhibit transcription of mutant Dmpk CTGexp genes. The overall objective of this project is to provide the DM field with more robust mouse models of DM1 while also evaluating splicing defects as biomarkers of disease status and developing single small molecule strategies

1型肌强直性营养不良（DM1），由3'非翻译区CTG扩张（CTGexp）引起