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Evaluation of adeno-associated viral (AAV) mediated gene replacement therapy as a therapeutic option for SLC25A4 deficiency

评估腺相关病毒 (AAV) 介导的基因替代疗法作为 SLC25A4 缺陷的治疗选择

基本信息

批准号：
10606065
负责人：
Abigail Benkert
金额：
$ 7.63万
依托单位：
DUKE UNIVERSITY
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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606065
关键词：
Adrenergic Agents Affect Base Pairing Biochemical Cardiac Myocytes Cardiomyopathies Cell Line Cell model Cells Codon Nucleotides Complementary DNA DNA Data Development Disease Disease Progression Evaluation Exertion Family Fellowship Foundations Frameshift Mutation Functional disorder Generations Goals Heart Transplantation Heart failure Hereditary Disease Hypertrophic Cardiomyopathy Impairment In Vitro Individual Inherited Inner mitochondrial membrane Laboratories Lactic Acidosis Link Mediating Mendelian disorder Mennonite Mitochondria Mitochondrial Proteins Modality Modeling Modification Molecular Muscle Cells Muscle Fibers Mutation Myocardial Myocardial dysfunction Myocardium Myopathy Natural History Nuclear Organ Organoids Oxidative Phosphorylation Patients Phenotype Pre-Clinical Model Protein Isoforms Proteins Recombinants Recovery Research Research Personnel SLC25A4 gene Scientist Secondary to Skeletal Development Skeletal Muscle Structure Surgeon Systemic Therapy Therapeutic Tissues Training Transgenes Translating Translational Research Translations Tropism Viral Viral Vector autosome career cohort delivery vehicle disease phenotype efficacy evaluation experimental study gene replacement gene replacement therapy genetic pedigree improved in vitro Model induced pluripotent stem cell loss of function member mitochondrial metabolism next generation null mutation premature prevent reduce symptoms restoration skeletal skills solute therapeutic gene treatment strategy vector vector biodistribution

项目摘要

Project Summary/Abstract Disruption of mitochondrial oxidative phosphorylation (OXPHOS) is associated with the development of biochemical alterations that typically affect tissues with a high energy demand, particularly skeletal and cardiac muscle. An inherited autosomal recessive skeletal myopathy and hypertrophic cardiomyopathy has been linked to loss of function of a nuclear DNA-encoded mitochondrial protein, due to a frameshift mutation in solute carrier family 25, member 4 (SLC25A4; c.523delC, p.Q175RfxX38). SLC25A4 encodes the heart-muscle isoform of the adenine nucleotide translocator-1 (ANT1, SLC25A4), which in the wild-type state is a critical component of mitochondrial metabolism. Patients with SLC25A4 deficiency display lactic acidosis, persistent adrenergic activation, and exertional intolerance secondary to both a general skeletal muscle myopathy as well as a hypertrophic cardiomyopathy. Ultimately, myocardial thickening and cardiac dysfunction progress to end- stage heart failure necessitating cardiac transplantation. There are not currently any disease-modifying therapies available for this patient cohort. However, adeno- associated viral (AAV) mediated gene replacement therapies have emerged as a powerful strategy for disease modification of inherited monogenic disorders. The long-term goal of our research is to develop a therapeutic gene replacement strategy to treat SLC25A4 deficiency. The objective of this proposal is to further characterize the disease phenotype as well as to synthesize and evaluate the efficacy of a recombinant AAV (rAAV) vector in an in vitro model of patient-derived cell lines and organoid models. The central hypothesis of this proposal is that AAV-mediated gene replacement can ameliorate the biochemical and functional effects of SLC25A4 deficiency and can more decisively prevent disease progression. The specific aims of this proposal are: 1. Characterize the SLC25A4 deficiency phenotype in patient-derived cell lines. 2. Synthesize a recombinant AAV vector for delivery of codon-optimized SLC25A4 cDNA to skeletal and cardiac myocytes. 3. Evaluate the efficacy of AAV-SLC25A4 viral transduction in patient-derived cell lines. These experiments will improve our understanding of the molecular mechanisms underlying SLC25A4 deficiency as well as allow us to evaluate the efficacy of an AAV platform in a relevant preclinical model. Moreover, the skills I will acquire during this fellowship will help to establish me as an independent investigator and a surgeon-scientist focused on the development of translational gene replacement therapies.

项目总结/摘要线粒体氧化磷酸化（OXPHOS）的破坏与以下疾病的发生有关：通常影响高能量需求组织的生化改变，特别是骨骼和心脏肌肉.一种遗传性常染色体隐性骨骼肌病和肥厚型心肌病有关联核DNA编码的线粒体蛋白功能丧失，由于溶质中的移码突变，携带者家族25，成员4（SLC 25 A4; c.523delC，p.Q175RfxX38）。SLC 25 A4编码心肌腺嘌呤核苷酸转运子-1（ANT 1，SLC 25 A4）的同种型，其在野生型状态下是一个关键的线粒体代谢的组成部分。具有SLC 25 A4缺乏的患者显示乳酸酸中毒，持续性肾上腺素能激活和继发于全身骨骼肌肌病的劳力性不耐受是肥厚型心肌病最终，心肌增厚和心功能障碍进展至结束- 需要心脏移植的阶段性心力衰竭。目前没有任何疾病缓解疗法可用于该患者队列。然而，腺- 相关病毒（AAV）介导的基因替代疗法已经成为治疗疾病的有力策略遗传性单基因疾病的修饰。我们研究的长期目标是开发一种治疗基因替代策略治疗SLC 25 A4缺陷。本提案的目的是进一步说明疾病表型以及合成和评估重组AAV（rAAV）载体的功效在患者来源的细胞系和类器官模型的体外模型中。这个问题的核心假设是我们认为，AAV介导的基因置换可以改善生物化学和功能效应， SLC 25 A4缺乏症，可以更果断地预防疾病进展。具体目标是建议如下： 1.表征患者来源细胞系中的SLC 25 A4缺陷表型。 2.合成用于递送密码子优化的SLC 25 A4 cDNA的重组AAV载体，骨骼肌和心肌细胞。 3.评估AAV-SLC 25 A4病毒转导在患者来源的细胞系中的功效。这些实验将提高我们对SLC 25 A4的分子机制的理解这一发现证实了AAV平台的缺陷，并且允许我们评估AAV平台在相关临床前模型中的功效。此外，我将获得的技能，在这个奖学金将有助于建立我作为一个独立的调查员一位外科医生兼科学家专注于翻译基因替代疗法的发展。