Models for Therapy of Hereditary Retinal Degenerations

描述(由申请者提供)：该项目致力于加速遗传性视网膜变性治疗新的有效方法的开发和临床前测试。这些疾病是导致人们失明的主要原因，影响着超过10万美国人，并且是由大量不同的基因突变引起的，而这些突变并不是所有的都被确定。类似的疾病也会影响狗，在许多情况下，这些疾病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。在这个项目中，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，并评估潜在的疾病预防、治疗或改善方法。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所涉及的分子机制的了解，以及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调查员与独立资助的调查员互动发起，以制定、实施和执行优化利用这些突变体的具体方案。将特别强调合作研究：i)开发主要针对视杆和/或视锥感光细胞的基因治疗载体，并在适当的犬模型中测试这些载体。例如，视锥特异性载体将在色觉减退的犬模型中进行测试，杆状特异性载体将在常染色体显性遗传性视网膜色素变性的犬模型中进行测试。Ii)确定新的犬遗传性视网膜变性的致病突变，并研究这些疾病发病的关键细胞生物学机制。例如，将确定导致3种犬锥杆营养不良的突变。这将允许这些模型用于基因特异性治疗研究。Iii)确定在疾病发生期间有利于光感受器死亡或存活的分子信号，并试图作为基因特异性治疗的辅助或替代来调节这样的过程。 公共卫生相关性：遗传性视网膜变性是导致人类失明的主要原因。在向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有效性进行测试并对其安全性进行评估。这项研究计划侧重于新基因疗法的开发和临床前原理测试，以恢复视网膜功能并防止受基因影响的视网膜退化。

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.