Models for Therapy of Hereditary Retinal Degenerations

项目总结/摘要 该项目的重点是加快开发和临床前测试的新的和有效的 遗传性视网膜变性的治疗方法。这些疾病是导致 失明的人，影响超过100，000美国人，是由大量不同的 基因突变，并不是所有的都已经被发现。类似的疾病也影响狗，在许多 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病例。在这个项目中， 将在一个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， 更好地了解这些疾病的遗传和发病机制， 疾病预防、治疗或改善的方法。 具有良好特征的视网膜疾病的特定犬品系将被维持、繁殖和制造。 提供给研究人员进行合作研究，目的是a）增加我们对 涉及这些疾病的分子机制和B）潜在的临床前评估 治疗有效利用这些突变体的合作将由校长发起 调查员与独立供资的调查员互动，以制定、实施和开展 这些突变体的最佳利用的特定方案。将特别强调 合作研究： i）开发主要靶向视杆和/或视锥光感受器的基因治疗载体，并测试这些载体 在适当的犬模型中的载体。例如，将在犬中测试视锥细胞特异性载体， 将在常染色体显性遗传的犬模型中测试色盲和视杆细胞特异性载体。 显性视网膜色素变性 ii）鉴定新的犬遗传性视网膜变性中的致病突变，并研究 细胞生物学机制对这些疾病的发病机理至关重要。例如， 将鉴定导致3只犬锥-杆营养不良的动物。这将使这些模型能够 用于基因特异性治疗研究。 iii）鉴定在光感受器的发病期间有利于光感受器死亡或存活的分子信号。 疾病，并试图调节这些过程作为辅助或替代基因特异性 治疗

Project Summary/Abstract 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 favoring 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.