Genetic screening and therapies for nemaline myopathies

线状肌病的基因筛查和治疗

• 批准号: 9093821
• 负责人: ALAN H. BEGGS
• 金额: $ 36.36万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093821
• 关键词: ACTA1 gene; Actins; Address; Adult; Affect; Biological Assay; Biological Models; Biology; Biopsy; Birth; Candidate Disease Gene; Cessation of life; Child; DNA; DNA Sequence; Data; Development; Diagnosis; Diagnostic tests; Disease; Disease model; Early Diagnosis; Eligibility Determination; End Point Assay; Ensure; FDA approved; Family; Future; Genes; Genetic; Genetic Screening; Genetic study; Genome; Genotype; Goals; Health; Innovative Therapy; Investigation; Knowledge; Lead; Maps; Medical; Medical Genetics; Modeling; Molecular; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Mutation Analysis; Myopathy; Nemaline Myopathies; Neonatal Screening; Neuromuscular Diseases; Newborn Infant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Preclinical Drug Evaluation; Preclinical Testing; Prenatal Diagnosis; Procedures; Public Health; Relative Risks; Sarcomeres; Skeletal Muscle; Staging; Testing; Therapeutic; Thin Filament; Transcript; Transgenic Organisms; Walking; Zebrafish; accurate diagnosis; base; carrier testing; clinical material; cohort; congenital myopathy; cost effective; design; early childhood; effective therapy; exome; exome sequencing; gene therapy; genetic analysis; genome sequencing; infancy; innovation; neuromuscular; next generation; novel therapeutics; prevent; prognostic; programs; rapid diagnosis; retinal rods; screening; skeletal; small molecule libraries

DESCRIPTION (provided by applicant): The long-term goals of this project are to complete our understanding of the genetic basis for the nemaline myopathies (NMs) with the aim of developing rapid genetic diagnostic tests suitable for newborn screening programs, and to develop effective and innovative therapies for one of the common causes of NM that would be identified through such screening. The nemaline myopathies are a genetically heterogeneous group of closely related congenital myopathies, defined on the basis of congenital presentation of moderate to profound skeletal muscle weakness and muscle biopsy revealing nemaline rods in myofibers of affected children. The unifying molecular feature of these conditions is that fact that six of the seven known genes encode components of the actin thin filament, making this a disease of the sarcomere. Despite extensive genetic investigations utilizing mapping and candidate gene analysis, the genetic basis for many cases remains unknown. However, the advent of next generation DNA sequencing, and availability of whole exome and genome sequencing makes comprehensive genetic studies feasible in a rapid and cost-effective manner. Whole exome sequencing will be utilized to complete the genetic analysis of a large and well- characterized cohort of NM patients, and on the basis of these results, a specific DNA capture chip will be designed to facilitate rapid analysis of all the genes for NM and related congenital myopathies for use in screening hypotonic and weak newborns. Effective therapies for NM are lacking, and a major hurdle to their development is absence of model systems suitable for screening potential therapeutic compounds. To address this problem, zebrafish models of skeletal actin (ACTA1 gene) related NM (NEM3) will be developed and characterized, and utilized in high throughput drug screens to identify lead compounds with therapeutic potential for NM and related disorders in patients with primary skeletal myopathies and muscular dystrophies. Development of this efficient and sensitive newborn DNA-based screening protocol will allow for rapid and accurate diagnosis, eliminating the need for more invasive and risky procedures such as muscle biopsy, and will allow for early prognostic determinations, carrier testing in at risk relatives to prevent births of future affected children, and will allow for optial early medical management. Identification of new therapeutic compounds and approaches will set the stage for preclinical testing of new therapies that may one day be used to treat children with these devastating neuromuscular diseases. These advances will also increase our knowledge of basic muscle biology with implications for our understanding of other neuromuscular diseases.

描述（由申请人提供）：该项目的长期目标是完成我们对线状性肌病（NMs）遗传基础的理解，目的是开发适合新生儿筛查项目的快速遗传诊断测试，并开发有效和创新的治疗方法，用于通过筛查确定的线状性肌病的常见原因之一。线状肌病是一组遗传异质性的密切相关的先天性肌病，其定义基于中度至重度骨骼肌无力的先天性表现和肌肉活检显示受影响儿童肌纤维中的线状棒。这些疾病的统一分子特征是，七个已知基因中有六个编码肌动蛋白细丝的成分，使其成为一种肌节疾病。尽管广泛的遗传调查利用作图和候选基因分析，遗传基础的许多情况下仍然未知。然而，下一代DNA测序的出现以及全外显子组和基因组测序的可用性使得全面的遗传研究以快速和经济的方式成为可能。全外显子组测序将用于完成一个庞大且特征明确的NM患者队列的遗传分析，并在这些结果的基础上，设计一个特定的DNA捕获芯片，以方便快速分析NM及相关先天性肌病的所有基因，用于筛选低张力和虚弱的新生儿。NM缺乏有效的治疗方法，其发展的主要障碍是缺乏适合筛选潜在治疗化合物的模型系统。为了解决这一问题，将开发和表征骨骼肌动蛋白（ACTA1基因）相关NM （NEM3）的斑马鱼模型，并将其用于高通量药物筛选，以鉴定具有治疗原发性骨骼肌病和肌肉营养不良患者NM及相关疾病潜力的先导化合物。这种高效和敏感的新生儿dna筛查方案的开发将允许快速和准确的诊断，消除对肌肉活检等更具侵入性和风险的程序的需要，并将允许早期预后确定，在有风险的亲属中进行携带者检测，以防止未来受影响儿童的出生，并将允许光学早期医疗管理。新的治疗化合物和方法的鉴定将为新疗法的临床前测试奠定基础，这些新疗法有一天可能被用于治疗患有这些破坏性神经肌肉疾病的儿童。这些进步也将增加我们对基本肌肉生物学的认识，并对我们对其他神经肌肉疾病的理解产生影响。