Mechanism-based therapies for photoreceptor degeneration

 描述(申请人提供)：光感受器退化和葡萄膜炎(眼内炎症)的分子靶点知之甚少。取得进展的一个主要障碍是缺乏任何特定的分子原因。这一建议建立在我们令人兴奋的发现钙激活的CAPN5(calain-5)作为常染色体显性遗传性新生血管炎性玻璃体视网膜病变(ADNIV)的原因的基础上。CAPN5是第一个非综合征性葡萄膜炎基因，为光感受器变性引起的炎症的机制治疗提供了一种高度创新的分子遗传学方法。光感受器表达CAPN5，在小鼠中hCAPN5-R243L功能突变的获得显示了人类ADNIV疾病的所有表型。视网膜光感受器可能对CAPN5的突变特别敏感，因为高细胞内钙是调节光感受器暗适应所必需的，也是足够的。我们的长期目标是找到更好、更具体的光感受器退化治疗方法。我们的目标是使用我们的新hCAPN5-R243L小鼠来确定阻断CAPN5活性是否可以抑制退化和葡萄膜炎。我们的中心假设是，钙激活的CAPN5途径会导致ADNIV视网膜变性和葡萄膜炎，我们的转基因CAPN5突变小鼠是测试几种新的葡萄膜炎疗法的最佳动物模型。我们的具体目标是(1)用药理上的CAPN5抑制剂治疗hCAPN5-R243L小鼠的光感受器退化，(2)用新型的双链shRNA基因沉默载体恢复hCAPN5-R243L小鼠的光感受器表型，(3)使用针对IL-6和IL-23的商用中和抗体治疗hCAPN5-R243L小鼠的葡萄膜炎。冲击力。我们希望建立hCAPN5-R243L小鼠作为有价值的动物模型，用于测试ADNIV的新疗法，并可移植到患者身上。我们的工作应该有助于确定钙激活的CAPN5信号在ADNIV和其他光感受器退化中的作用。由于hCAPN5-R243L疾病在其他形式的葡萄膜炎中被发现与其他伴有感光细胞变性的眼部疾病和CAPN5途径的组成部分有关，我们的研究可能会产生广泛的积极影响，超越ADNIV和葡萄膜炎患者，这些患者的CAPN5途径的组成部分可能是治疗靶点。

 DESCRIPTION (provided by applicant): The molecular targets for photoreceptor degenerations and uveitis (intraocular inflammation) are poorly understood. A major barrier to progress has been the lack of any specific molecular cause. This proposal builds on our exciting discovery of calcium-activated CAPN5 (calpain-5) as the cause of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). CAPN5 is the first nonsyndromic uveitis gene, and makes possible a highly innovative molecular-genetic approach for mechanism-based therapies for inflammation induced by photoreceptor degeneration. Photoreceptors express CAPN5, and an hCAPN5- R243L gain of function mutation in mice shows all the phenotypes of human ADNIV disease. The retina photoreceptors might be particularly sensitive to mutations in CAPN5, because high intracellular calcium is necessary and sufficient to regulate dark adaptation in photoreceptors. Our long-term goals are to find better and more specific treatments for photoreceptor degeneration. Our objective is to use our new hCAPN5-R243L mice to determine whether blocking CAPN5 activity can inhibit degeneration and uveitis. Our central hypothesis is that a calcium-activated CAPN5 pathway leads to ADNIV retinal degeneration and uveitis, and our transgenic CAPN5 mutant mouse is the best available animal model for testing several new uveitis therapies. Our specific aims are to (1) Treat photoreceptor degeneration in hCAPN5-R243L mice with a pharmacological CAPN5 inhibitor, (2) Rescue the photoreceptor phenotype in hCAPN5-R243L mice with a novel bipartite shRNA gene silencing vector, and (3) Treat uveitis in hCAPN5-R243L mice using commercially available neutralizing antibodies targeting IL-6 and IL-23. Impact. We expect to establish the hCAPN5-R243L mouse as a valuable animal model for testing novel therapies in ADNIV, which can be translated to patients. Our work should help determine the role of of calcium-activated CAPN5 signaling in ADNIV and other photoreceptor degenerations. Since hCAPN5-R243L disease stages phenocopy other eye diseases with photoreceptor degeneration and components of the CAPN5 pathway are found in other forms of uveitis, our studies could have a broad, positive impact, beyond ADNIV and uveitis patients, where components of the CAPN5 pathway may be therapeutic targets.