Models for Therapy of Hereditary Retinal Degenerations

项目描述（由申请人提供）：本项目致力于加速遗传性视网膜变性治疗新有效方法的开发和临床前试验。这些疾病是导致人们失明的主要原因，影响了超过10万美国人，它们是由大量不同的基因突变引起的，但并非所有的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，它们是由与人类相同或基本相似的基因突变引起的。本项目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，并评估潜在的疾病预防、治疗或改善方法。具有视网膜疾病特征的特定犬系将被维持、繁殖，并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的分子机制的理解；b)潜在治疗方法的临床前评估。有效利用这些突变体的合作将由首席研究人员与独立资助的研究人员互动发起，以制定、实施和执行最佳利用这些突变体的具体协议。将特别强调合作研究：i)开发主要针对杆状和/或锥状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，锥体特异性载体将在犬色盲模型中进行测试，棒状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，突变负责3犬锥杆营养不良症将被确定。这将允许这些模型用于基因特异性治疗研究。iii)识别在疾病发病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，作为基因特异性治疗的辅助或替代方法。

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.