ERG assessment of altered retinal function in canine models of retinitis pigmentosa and monitoring of response to translatable gene augmentation therapy.
ERG assessment of altered retinal function in canine models of retinitis pigmentosa and monitoring of response to translatable gene augmentation therapy.
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DOI：
10.1007/s10633-021-09832-0
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Petersen-Jones SM
中科院分区：
文献类型：
--
作者：
Pasmanter N;Occelli LM;Petersen-Jones SM
目的：分析由PDE6A突变和CNGB1突变引起的两种视网膜色素变性犬模型的ERG反应，以评估这些突变对视网膜功能的影响以及基因增强治疗恢复正常功能的能力。分析了AAV介导的基因增强治疗后，年轻的患病犬、正常对照犬和患病犬的暗视和明视ERG。通过模拟a波的下降斜率，收集反映视杆和视锥功能的参数，以测量受体的反应和灵敏度。通过对暗视b波亮度：反应图的第一个肢体的Naka-Rushton拟合，进一步评估杆驱动的反应。PDE6A−/−犬的杆状驱动反应显著降低，杆状最大反应和敏感度显著降低。最大锥体反应的波幅略有降低。与之相反，CNGB1−/−犬有部分残留的杆状反应，波幅和灵敏度降低，锥体反应正常。基因增强治疗后，两种模型视杆参数均有明显改善，敏感参数logS和logK恢复正常，且logRmax有较大幅度增加，与治疗后视网膜区域正常视杆转导功能的恢复相一致。视杆细胞和视锥细胞a波模型和暗视b波的亮度反应函数表征了两种视网膜色素变性犬模型视杆细胞光感受器功能的丧失，显示了基因增强治疗在恢复正常功能参数方面的有效性。
To analyze ERG responses from two dog models of retinitis pigmentosa, one due to a PDE6A mutation and the other a CNGB1 mutation, both to assess the effect of these mutations on retinal function and the ability of gene augmentation therapy to restore normal function. Scotopic and photopic ERGs from young affected and normal control dogs and affected dogs following AAV-mediated gene augmentation therapy were analyzed. Parameters reflecting rod and cone function were collected by modeling the descending slope of the a-wave to measure receptor response and sensitivity. Rod-driven responses were further assessed by Naka-Rushton fitting of the first limb of the scotopic b-wave luminance:response plot. PDE6A−/− dogs showed a dramatic decrease in rod-driven responses with very reduced rod maximal responses and sensitivity. There was a minor reduction in the amplitude of maximal cone responses. In contrast, CNGB1−/− dogs had some residual rod responses with reduced amplitude and sensitivity and normal cone responses. Following gene augmentation therapy rod parameters were substantially improved in both models with restoration of sensitivity parameters log S and log K and a large increase in log Rmax in keeping with rescue of normal rod phototransduction in the treated retinal regions. Modeling of rod and cone a-waves and the luminance:response function of the scotopic b-wave characterized the loss of rod photoreceptor function in two dog models of retinitis pigmentosa and showed the effectiveness of gene augmentation therapy in restoring normal functional parameters.
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