Simon Cardillia-Joe, Khabou Hanen, Chaffiol Antoine, Rucli Marco, Finzi Marion, Norberg Nat, Grimaud Anaïs, Mücher Brix, Desrosiers Mélissa, Sancho Serge, Bonilha Vera Lucia, Grieve Kate, Duebel Jens, Paques Michel, Picaud Serge, Sahel José Alain, Audo Isabelle, Herlitze Stefan, Dalkara Deniz
Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
Gamut Therapeutics, 4 rue Thénard, 75005 Paris, France.
iScience. 2025 Feb 25;28(4):112106. doi: 10.1016/j.isci.2025.112106. eCollection 2025 Apr 18.
Rod-cone dystrophy (RCD) comprises genetic conditions where rod photoreceptor degeneration leads to cone loss, causing progressive vision loss. We investigated the phototransduction cascade in degenerating cones using two RCD mouse models and found that opsin and arrestin expression continues in the cell body during outer segment degeneration. Based on this observation, we explored reactivating cones through G-protein-coupled inwardly rectifying K (GIRK) channel expression. Using adeno-associated viral delivery of GIRK channels, we achieved improved visual function in both mouse models. Additionally, we examined human tissue from late-stage RCD patients and confirmed the presence of cone opsin and cone arrestin expression, supporting the potential therapeutic application of this approach. This GIRK-channel-based strategy offers a promising method to preserve high-quality vision in RCD patients, regardless of their specific genetic mutation.
视杆-视锥营养不良（RCD）包括多种遗传性疾病，其中视杆光感受器变性会导致视锥细胞丧失，进而引起进行性视力丧失。我们使用两种RCD小鼠模型研究了退化视锥细胞中的光转导级联反应，发现视蛋白和抑制蛋白的表达在外段退化过程中仍在细胞体内持续存在。基于这一观察结果，我们探索了通过G蛋白偶联内向整流钾通道（GIRK）的表达来使视锥细胞重新激活。通过腺相关病毒递送GIRK通道，我们在两种小鼠模型中均实现了视觉功能的改善。此外，我们检查了晚期RCD患者的人体组织，并证实了视锥视蛋白和视锥抑制蛋白的表达，支持了这种方法的潜在治疗应用。这种基于GIRK通道的策略为在RCD患者中保留高质量视力提供了一种有前景的方法，无论其具体的基因突变如何。
