Gene Therapy Design Principles for Duchenne Muscular Dystrophy
杜氏肌营养不良症的基因治疗设计原则
基本信息
- 批准号:10723951
- 负责人:
- 金额:$ 16.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvisory CommitteesAffectAwardBiochemicalBiochemistryBiological AssayBiomedical EngineeringCalciumCardiacCardiac MyocytesCardiomyopathiesCardiovascular DiseasesCardiovascular systemCell DeathCell SurvivalCell membraneCellsCellular MorphologyCellular biologyCicatrixCodeContractsCytoskeletal ProteinsDataDefectDependovirusDevelopment PlansDilatation - actionDilated CardiomyopathyDiseaseDisease ProgressionDisease modelDuchenne cardiomyopathyDuchenne muscular dystrophyDyesDystrophinEchocardiographyEngineeringEnsureExhibitsExtracellular MatrixFibrosisFunctional disorderHeartHeart DiseasesHeart failureHistologyHumanHydrogelsImageImpairmentLearningLeft ventricular structureLengthLifeLongevityLuciferasesMeasuresMendelian disorderMentored Research Scientist Development AwardMentorsMentorshipMethodsMicroscopyMuscleMuscular dystrophy cardiomyopathyMutationOnset of illnessPathogenicityPathologicPatientsPhenotypeProteinsQuality of lifeReactive Oxygen SpeciesReporterResearchResearch PersonnelRespiratory FailureSkeletal MuscleStroke VolumeSymptomsTechniquesTelomere ShorteningTestingTherapeutic EffectThinnessTissuesTraction Force MicroscopyTrainingVariantVentricularWestern Blottingadeno-associated viral vectorcareercareer developmentdesignefficacy evaluationexperimental studygene therapyheart functionimprovedinduced pluripotent stem cellinnovationlink proteinlipid nanoparticlemalemouse modelmuscle degenerationmutation correctionnanoparticle deliverynovelpediatric cardiologistprematurepreventprogramspromoterprotein expressionratiometricreduce symptomsresponserestorationskeletal muscle wastingskillstelomeretherapy designvector
项目摘要
Project Summary/Abstract
The long-term objective of this study is to develop gene therapies that treat Duchenne muscular dystrophy (DMD)
cardiomyopathy. DMD cardiomyopathy, characterized by ventricular chamber enlargement and thinning of the
ventricular wall, ultimately leads to heart failure. Pathogenic features of DMD cardiomyocytes include contractile
dysfunction, poor calcium handling, elevated reactive oxygen species, telomere shortening, and premature cell
death. When a large number of cells die in the heart, scar tissue forms, increasing the stiffness of the heart.
Although there are treatments available to alleviate symptoms of dilated cardiomyopathy, there are currently no
therapies to prevent or delay the onset of this disease. Smaller versions of dystrophin amenable to gene therapy
have shown promise to treat DMD-associated severe skeletal muscle wasting; however, surprisingly little is
known about their effects in treating heart failure. This research plan will leverage bioengineered hydrogels of
tunable stiffness, human induced pluripotent stem cells (iPSCs) with dystrophin mutations, and biochemical
techniques to determine if full-length dystrophin can rescue DMD cardiomyocytes from their pathogenic demise.
During the K01 award period, Dr. Asuka Eguchi will train under the mentorship of Dr. Helen Blau, an expert on
DMD. By engineering hydrogels that mimic stiff, diseased heart tissue, Dr. Eguchi will be able to measure
parameters of contraction in cardiomyocytes differentiated from DMD iPSCs. Aim 1 will test if full-length
dystrophin can rescue DMD cardiomyocytes from contractile deficits, aberrant calcium handling, and premature
cell death. Aim 2 will determine if split vector or lipid nanoparticle approaches can deliver full-length dystrophin
to cardiomyocytes. Aim 3 will test whether this gene therapy strategy to deliver full-length dystrophin can delay
the onset of DMD cardiomyopathy in a mouse model. Gene therapy approaches targeting the root cause of
disease, the lack of dystrophin, is critical for extending lifespan and improving the quality of life of DMD patients.
The career development plan is designed to enable Dr. Eguchi to successfully transition to a career as
independent investigator. Her scientific advisory committee consist of Dr. Beth Pruitt, a bioengineer with
expertise in traction force microscopy, Dr. Joseph Wu, an expert on cardiovascular disease modeling, and Dr.
Daniel Bernstein, a pediatric cardiologist. Collectively, these collaborators will help Dr. Eguchi develop skills at
the interface of bioengineering, cell biology, and biochemistry to launch an independent research program in
cardiovascular research.
项目摘要/摘要
这项研究的长期目的是开发治疗Duchenne肌肉营养不良(DMD)的基因疗法
心肌病。 DMD心肌病,其特征是心室室肿大和变薄
心室壁,最终导致心力衰竭。 DMD心肌细胞的致病特征包括收缩
功能障碍,钙处理不良,活性氧升高,端粒缩短和过早细胞
死亡。当大量细胞在心脏中死亡时,会形成疤痕组织,从而增加心脏的刚度。
尽管有治疗方法可缓解扩张心肌病的症状,但目前没有
预防或延迟这种疾病发作的疗法。较小版本的肌营养不良蛋白可适应基因治疗
已经显示出有望治疗与DMD相关的严重骨骼肌浪费的承诺;但是,令人惊讶的是
知道它们在治疗心力衰竭方面的影响。该研究计划将利用
可调刚度,人体诱导的多能干细胞(IPSC)具有肌营养不良蛋白突变和生化
确定全长肌营养不良蛋白是否可以从致病性灭亡中挽救DMD心肌细胞的技术。
在K01奖项期间,Asuka Eguchi博士将在Helen Blau博士的指导下进行培训。
DMD。通过工程水凝胶模仿僵硬,患病的心脏组织,Eguchi博士将能够测量
与DMD IPSC区分开的心肌细胞收缩参数。 AIM 1将测试是否全长
肌营养不良蛋白可以从收缩缺陷,异常钙处理和早产中挽救DMD心肌细胞
细胞死亡。 AIM 2将确定分裂载体或脂质纳米颗粒方法是否可以提供全长肌营养不良蛋白
到心肌细胞。 AIM 3将测试这种基因治疗策略是否提供全长肌营养不良蛋白会延迟
小鼠模型中DMD心肌病的发作。基因治疗方法针对的根本原因
疾病(缺乏肌营养不良蛋白)对于延长寿命和改善DMD患者的生活质量至关重要。
职业发展计划旨在使Eguchi博士成功过渡到职业
独立研究者。她的科学咨询委员会由Beth Pruitt博士组成,他是一名生物工程师
牵引力显微镜的专业知识,心血管疾病建模专家约瑟夫·吴(Joseph Wu)博士和博士
丹尼尔·伯恩斯坦(Daniel Bernstein),儿科心脏病专家。总的来说,这些合作者将帮助Eguchi博士在
生物工程,细胞生物学和生物化学的界面启动独立研究计划
心血管研究。
项目成果
期刊论文数量(0)
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