Chew Lindsey A, Grigsby Daniel, Hester C Garren, Amason Joshua, McPherson W Kyle, Flynn Edward J, Visel Meike, Starr Christopher R, Flannery John G, Lewis Tylor R, Bowes Rickman Catherine
Department of Ophthalmology, Duke Eye Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Genetically Engineered Murine Model (GEMM) Core, University of Virginia, Charlottesville, VA 22903, USA.
Mol Ther. 2025 Apr 24. doi: 10.1016/j.ymthe.2025.04.035.
There are no effective therapies for patients with dry age-related macular degeneration (AMD) or C3 glomerulonephritis (C3G). Unfortunately, past efforts to treat C3G using exogenous human complement factor H (CFH) found limited success due to immune rejection of a foreign protein response. AMD research has also faced myriad challenges, including the absence of an ideal therapeutic target and difficulties with treatment delivery in certain preclinical models. In pursuit of an AMD therapy to overcome these obstacles, we ultimately capitalized on parallels in complement dysregulation between AMD and C3G. Here, we investigate the potential for CFH supplementation as a strategy to rescue C3G. Our findings demonstrate restored inhibition of complement's alternative pathway and long-term reversal of disease without immune rejection using adeno-associated virus (AAV)-mediated delivery of truncated CFH (tCFH) in a Cfh mouse model of C3G. We tested three different tCFH vectors and found significant differences in their relative transduction efficiency and therapeutic efficacy. These discoveries motivate the development of AAV-mediated tCFH replacement therapy for patients with C3G while simultaneously demonstrating proof of concept for AAV-mediated tCFH gene augmentation therapy for patients with AMD.
对于干性年龄相关性黄斑变性（AMD）或C3肾小球肾炎（C3G）患者，目前尚无有效的治疗方法。不幸的是，过去使用外源性人补体因子H（CFH）治疗C3G的努力因对外源蛋白反应的免疫排斥而成效有限。AMD研究也面临着诸多挑战，包括缺乏理想的治疗靶点以及在某些临床前模型中治疗给药困难。为了寻找一种克服这些障碍的AMD治疗方法，我们最终利用了AMD和C3G在补体失调方面的相似之处。在此，我们研究补充CFH作为挽救C3G的一种策略的潜力。我们的研究结果表明，在C3G的Cfh小鼠模型中，使用腺相关病毒（AAV）介导的截短型CFH（tCFH）递送，可恢复对补体替代途径的抑制，并实现疾病的长期逆转且无免疫排斥反应。我们测试了三种不同的tCFH载体，发现它们的相对转导效率和治疗效果存在显著差异。这些发现推动了针对C3G患者的AAV介导的tCFH替代疗法的开发，同时也为针对AMD患者的AAV介导的tCFH基因增强疗法提供了概念验证。
