Models for Therapy of Hereditary Retinal Degenerations

项目摘要/摘要 该项目致力于加快开发和临床前测试新的有效的 遗传性视网膜变性的治疗方法。这些疾病是导致 在人群中失明，影响着超过10万美国人，并且是由大量不同的 基因突变，并不是所有的基因突变都被识别出来。类似的疾病也会影响狗，在许多情况下 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， 研究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，以 更好地了解这些疾病的遗传和致病机制，并评估潜在的 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种将被维护、培育和制造 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 调查员与独立资助的调查员互动，以开发、实施和实施 最大限度地利用这些突变体的特定方案。我们将特别强调 具有以下特点的协作研究： I)开发主要针对视杆和/或视锥感光细胞的基因治疗载体，并对其进行测试 在适当的犬类模型中传播媒介。例如，锥体特异性载体将在犬类身上进行测试 色盲模型和杆状特异载体将在常染色体犬类模型中进行测试 显性视网膜色素变性。 Ii)确定新的犬遗传性视网膜变性的致病突变，并调查 对此类疾病的发病至关重要的细胞生物学机制。例如，突变 将确定3只犬齿锥杆营养不良的负责人。这将允许这些模型 用于基因特异性治疗研究。 三)确定有利于光感受器在发病期间死亡或存活的分子信号 疾病，并试图调节这样的过程，作为基因特异性的辅助或替代 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.