Targeted Inhibition of NMD to Enhance the Efficacy of Readthrough Drugs
靶向抑制NMD以增强通读药物的疗效
基本信息
- 批准号:8429753
- 负责人:
- 金额:$ 23.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAge of OnsetAge-YearsAllelesAminoglycoside AntibioticsAntisense OligonucleotidesBindingBypassCell Culture TechniquesCell LineCellsComplexCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDepositionDigestionDiseaseDrug usageDuchenne muscular dystrophyEffectivenessExonsFutureGene ExpressionGene ProteinsGenesGenetic screening methodGoalsHereditary DiseaseHuman Genome ProjectImmunoprecipitationIn VitroIndividualLaboratoriesLeadLengthMapsMediatingMessenger RNAMethodsMicrococcal NucleaseMolecularMutationNeonatalNonsense CodonNonsense MutationNucleotidesOutcomeOutputPathway interactionsPatientsPerformancePharmaceutical PreparationsProductionProteinsQuality ControlRNARNA BindingRNA SplicingRadioactiveReporterRett SyndromeReverse Transcriptase Polymerase Chain ReactionRibosomesSMN2 geneSignal TransductionSpinal Muscular AtrophySymptomsTechnologyTestingTherapeuticTranscriptTranslationsbasebeta Thalassemiadesigneffective therapyimprovedin vivoknock-downmRNA DecaymRNA Precursormutantnovelnovel strategiesphosphorothioatepreventresearch studytool
项目摘要
DESCRIPTION (provided by applicant): The successful completion of the human genome project and mapping of many disease genes, combined with advances in the molecular understanding of gene-expression pathways, provides unprecedented opportunities to design novel mechanism-based therapies for various genetic diseases. Nonsense mutations account for a large fraction of the causal mutations in nearly all genetic diseases. By definition, nonsense mutations introduce premature termination codons (PTCs), resulting in truncated proteins, and usually severe disease presentations. Translational readthrough drugs, such as ataluren, allow the synthesis of some full-length, functional protein from defective genes with nonsense mutations. However, nonsense-mediated mRNA decay (NMD)¿a ubiquitous mRNA quality-control pathway¿diminishes the effectiveness of readthrough drugs. We will selectively abrogate NMD of mRNAs harboring PTCs, so as to increase their availability for readthrough drugs. To explore the feasibility of our approach, we will initially focus on cell-culture experiments with several nonsense alleles of CFTR, MECP2, DMD, and HBB genes, which cause cystic fibrosis, Rett syndrome, Duchenne muscular dystrophy, and beta-thalassemia, respectively. We will systematically test the effect of inhibiting NMD on mRNA accumulation. Using reporter cell lines, we will then combine transcript-specific NMD inhibition with ataluren treatment, and determine whether there is increased synthesis of full-length protein, compared to ataluren treatment alone. The results of this exploratory study are expected to provide proof of principle for the effectiveness of targeted inhibition of NMD to enhance the efficacy of readthrough drugs. The proposed experiments could lead to a broadly applicable therapeutic approach that would be used in combination with readthrough drugs to treat a large number of severe genetic diseases.
PUBLIC HEALTH RELEVANCE: Nonsense mutations result in truncated protein production and cause many severe genetic diseases. Drugs like ataluren can promote the synthesis of intact proteins from genes with nonsense mutations; however, cells have an intrinsic mechanism that diminishes the output of genes with nonsense mutations. We will develop a method to bypass this mechanism for individual mutant genes, so as to enhance the effectiveness of ataluren and similar drugs, and thereby provide more effective therapies for a variety of genetic diseases.
描述(由申请人提供):人类基因组计划的成功完成和许多疾病基因的定位,加上对基因表达途径的分子理解的进展,为设计各种遗传疾病的基于机制的新疗法提供了前所未有的机会。在几乎所有的遗传疾病中,无义突变占因果突变的很大一部分。根据定义,无义突变引入过早终止密码子(ptc),导致蛋白质截短,通常导致严重的疾病表现。转译读通药物,如ataluren,允许从无义突变的缺陷基因合成一些全长的功能性蛋白质。然而,无义介导的mRNA衰变(NMD) -一种普遍存在的mRNA质量控制途径-降低了读透药物的有效性。我们将有选择地取消含有ptc的mrna的NMD,以增加其在可读药物中的可用性。为了探索我们方法的可行性,我们将首先关注CFTR、MECP2、DMD和HBB基因的几个无义等位基因的细胞培养实验,这些基因分别导致囊性纤维化、Rett综合征、杜氏肌营养不良和-地中海贫血。我们将系统地测试抑制NMD对mRNA积累的影响。利用报告细胞系,我们将结合转录特异性NMD抑制与失钙素处理,并确定与单独失钙素处理相比,是否有全长蛋白合成增加。本探索性研究的结果有望为靶向抑制NMD的有效性提供原理证明,从而提高读通药物的疗效。拟议的实验可能会导致一种广泛适用的治疗方法,该方法将与read - through药物结合使用,用于治疗大量严重的遗传疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)
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Adrian R Krainer其他文献
A splicing component adapted to gene silencing
一种适用于基因沉默的剪接成分
- DOI:
10.1038/nbt0309-250 - 发表时间:
2009-03-01 - 期刊:
- 影响因子:41.700
- 作者:
Xavier Roca;Adrian R Krainer - 通讯作者:
Adrian R Krainer
A generalizable pre-clinical research approach for orphan disease therapy
- DOI:
10.1186/1750-1172-7-39 - 发表时间:
2012-06-15 - 期刊:
- 影响因子:3.500
- 作者:
Chandree L Beaulieu;Mark E Samuels;Sean Ekins;Christopher R McMaster;Aled M Edwards;Adrian R Krainer;Geoffrey G Hicks;Brendan J Frey;Kym M Boycott;Alex E MacKenzie - 通讯作者:
Alex E MacKenzie
Adrian R Krainer的其他文献
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{{ truncateString('Adrian R Krainer', 18)}}的其他基金
Regulation of Pre-mRNA Splicing in Tumorigenesis
肿瘤发生中前体 mRNA 剪接的调控
- 批准号:
8234411 - 财政年份:2012
- 资助金额:
$ 23.54万 - 项目类别:
Targeted Inhibition of NMD to Enhance the Efficacy of Readthrough Drugs
靶向抑制NMD以增强通读药物的疗效
- 批准号:
8536425 - 财政年份:2012
- 资助金额:
$ 23.54万 - 项目类别:
2008 The Biology of Post-Transcriptional Gene Regulation Gordon Research Conferen
2008 转录后基因调控生物学戈登研究会议
- 批准号:
7476630 - 财政年份:2008
- 资助金额:
$ 23.54万 - 项目类别:
Regulation of Pre-mRNA Splicing in Tumorigenesis
肿瘤发生中前体 mRNA 剪接的调控
- 批准号:
7225417 - 财政年份:2007
- 资助金额:
$ 23.54万 - 项目类别:
Design of molecules that promote SMN2 exon 7 inclusion
促进 SMN2 外显子 7 包含的分子设计
- 批准号:
6335699 - 财政年份:2001
- 资助金额:
$ 23.54万 - 项目类别:
Design of molecules that promote SMN2 exon 7 inclusion
促进 SMN2 外显子 7 包含的分子设计
- 批准号:
6540449 - 财政年份:2001
- 资助金额:
$ 23.54万 - 项目类别:
Design of molecules that promote SMN2 exon 7 inclusion
促进 SMN2 外显子 7 包含的分子设计
- 批准号:
6639771 - 财政年份:2001
- 资助金额:
$ 23.54万 - 项目类别:
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