Models for Therapy of Hereditary Retinal Degenerations

描述（由申请人提供）：该项目的重点是加速开发和临床前测试的新的和有效的方法来治疗遗传性视网膜变性。这些疾病是人类失明的主要原因，影响了超过10万美国人，并且是由大量不同的基因突变引起的，并非所有这些基因突变都已被确定。类似的疾病也会影响狗，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。在本项目中，将在受这种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，并评估预防、治疗或改善疾病的潜在方法。将对具有良好特征的视网膜疾病的特定犬种进行维持、繁殖，并提供给研究人员进行合作研究，旨在a）增加我们对这些疾病所涉及的分子机制的了解，以及B）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者与独立资助的研究者互动发起，以制定、实施和实施特定方案，以优化这些突变体的利用。将特别强调以下合作研究：i）开发主要针对视杆和/或视锥光感受器的基因治疗载体，并在适当的犬模型中测试这些载体。例如，视锥细胞特异性载体将在色盲犬模型中进行测试，视杆细胞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）鉴定新的犬遗传性视网膜变性中的致病突变，并研究对此类疾病的发病机理至关重要的细胞生物学机制。例如，将鉴定导致3种犬视锥-视杆营养不良的突变。这将允许这些模型用于基因特异性治疗研究。iii）鉴定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对其进行有效性测试和安全性评估。这项研究计划的重点是新基因疗法的开发和临床前原理验证测试，以恢复视网膜功能并预防遗传性视网膜变性。

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.