PDF(Pubmed)
Abstract：
Age-related macular degeneration (AMD) is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of AMD that has the appearance of the \"dry\" form, or geographic atrophy. Biallelic variants in CDHR1-a specialized protocadherin highly expressed in cone and rod photoreceptors-result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional, and behavioral rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months after injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy seems to be near complete-with morphological findings of the rescued retina not obviously different from wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry AMD. Accurate clinical classification is now critical, as their pathogenesis and treatment are distinct.
摘要：
年龄相关性黄斑变性（AMD）是发达国家无法治愈的失明的最常见原因。最近,CDHR1已被确定为具有“干”形式外观的AMD子集的原因，或地理萎缩。CDHR1的双等位基因变体-一种在视锥和视杆光感受器中高度表达的专门的原钙粘蛋白-导致光感受器外节缩短和进行性光感受器细胞死亡而失明。在这里，我们展示了长期的形态学，超微结构，功能，在相关的小鼠模型中，CDHR1基因治疗后的行为拯救，持续到注射后23个月。这代表了在体内挽救单基因钙粘蛋白病的首次证明。此外，CDHR1基因治疗的持久性似乎接近完全-在小鼠模型的整个生命周期中，获救视网膜的形态学发现与野生型没有明显差异。有必要对CDHR1相关视网膜变性患者进行后续临床试验。低态CDHR1变体可能模拟晚期干性AMD。准确的临床分类现在至关重要，因为它们的发病机制和治疗是不同的。
