Models for Therapy of Hereditary Retinal Degenerations

遗传性视网膜变性的治疗模型

• 批准号: 7995945
• 负责人: GREGORY M ACLAND
• 金额: $ 79.51万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995945
• 关键词: Affect; American; Automobile Driving; Biological Models; Blindness; Breeding; Canis familiaris; Cells; Cessation of life; Clinical Trials; Collaborations; Data; Development; Disease; Effectiveness; Ensure; Evaluation; Funding; Gene Mutation; Gene Transduction Agent; Genes; Genetic; Goals; Hereditary Disease; Housing; Human; Human Resources; Inherited; Institutes; Investigation; Lead; Mediating; Methods; Modeling; Molecular; Monitor; Mutation; Onset of illness; Pathogenesis; Photoreceptors; Prevention therapy; Principal Investigator; Process; Productivity; Progress Reports; Protocols documentation; RPE65 protein; Reproductive Health; Research; Research Personnel; Research Proposals; Resources; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Safety; Series; Signal Transduction; Speed; Testing; Therapy Clinical Trials; Vision; achromatopsia; clinically relevant; cohort; disorder prevention; experience; gene therapy; mutant; novel; pre-clinical; preclinical evaluation; prevent; programs; public health relevance; research clinical testing; research facility; response; retinal rods; success; vector

DESCRIPTION (provided by applicant): This project is focused on accelerating the development and pre-clinical testing of new and effective approaches to therapy of hereditary retinal degenerations. These diseases are a major cause of blindness in people, affecting over 100,000 Americans, and are caused by a large number of different gene mutations, not all of which have yet been identified. Similar diseases also affect dogs, in many cases caused by identical or essentially similar gene mutations to those affecting people. In this project, studies will be undertaken in a research colony of dogs affected by such hereditary retinal diseases to better understand the genetic and pathogenetic mechanisms of these diseases, and evaluate potential methods of disease prevention, therapy or amelioration. Specific canine strains with well characterized retinal disorders will be maintained, bred, and made available to research investigators for collaborative studies aimed at a) increasing our understanding of the molecular mechanisms involved in these diseases and b) preclinical evaluation of potential therapies. Collaborations to effectively utilize these mutants will be initiated by the Principal Investigators interacting with independently funded investigators, to develop, implement and conduct specific protocols for optimal utilization of these mutants. Special emphasis will be placed on collaborative studies that: i) develop vectors for gene therapy that primarily target rod and/or cone photoreceptors, and test these vectors in appropriate canine models. For example, cone-specific vectors will be tested in canine models of achromatopsia, and rod-specific vectors will be tested in a canine model of autosomal dominant retinitis pigmentosa. ii) identify the causative mutations in new canine hereditary retinal degenerations, and investigate the cell biologic mechanisms critical to the pathogenesis of such diseases. For example, the mutations responsible for 3 canine cone-rod dystrophies will be identified. This will then allow these models to be used for gene-specific therapy studies. iii) Identify molecular signals that favor either the death or survival of photoreceptors during the onset of disease, and attempt to modulate such processes as either an adjunct or alternative to gene-specific therapies. PUBLIC HEALTH RELEVANCE: Hereditary retinal degenerations are a major cause of human blindness. Before potential therapies can be made available for affected people it is essential that they be tested for effectiveness and evaluated for safety in appropriate clinically relevant model systems. This research proposal focuses on the development and preclinical proof of principle testing of new gene therapies to restore retinal function and prevent degeneration in genetically affected retinas.

描述（由申请人提供）：该项目的重点是加速遗传性视网膜变性治疗新有效方法的开发和临床前测试。这些疾病是导致人类失明的主要原因，影响着超过 100,000 名美国人，并且是由大量不同的基因突变引起的，但尚未确定所有这些突变。类似的疾病也影响狗，在许多情况下是由与影响人类的基因突变相同或基本相似的基因突变引起的。在该项目中，将在受此类遗传性视网膜疾病影响的狗的研究群体中进行研究，以更好地了解这些疾病的遗传和发病机制，并评估疾病预防、治疗或改善的潜在方法。将维持、培育具有明确特征的视网膜疾病的特定犬种，并将其提供给研究人员进行合作研究，目的是：a）增加我们对这些疾病所涉及的分子机制的理解；b）对潜在疗法的临床前评估。有效利用这些突变体的合作将由主要研究人员与独立资助的研究人员互动发起，以开发、实施和实施具体方案以优化利用这些突变体。将特别强调合作研究：i）开发主要针对视杆细胞和/或视锥细胞光感受器的基因治疗载体，并在适当的犬科动物模型中测试这些载体。例如，视锥特异性载体将在色盲犬模型中进行测试，视杆特异性载体将在常染色体显性视网膜色素变性犬模型中进行测试。 ii) 确定新的犬遗传性视网膜变性的致病突变，并研究对此类疾病发病机制至关重要的细胞生物学机制。例如，将鉴定导致 3 种犬视杆细胞营养不良的突变。这将使这些模型能够用于基因特异性治疗研究。 iii) 识别在疾病发作期间有利于光感受器死亡或存活的分子信号，并尝试调节这些过程作为基因特异性疗法的辅助或替代。 公共卫生相关性：遗传性视网膜变性是人类失明的主要原因。在为受影响的人提供潜在的治疗方法之前，必须在适当的临床相关模型系统中测试其有效性并评估其安全性。该研究计划的重点是新基因疗法的开发和临床前原理测试证明，以恢复视网膜功能并防止受遗传影响的视网膜退化。