Purpose

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.

Methods

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.

Results

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 R_max in keeping with rescue of normal rod phototransduction in the treated retinal regions.

Conclusions

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.

中文翻译：

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ERG 评估犬色素性视网膜炎模型中改变的视网膜功能并监测对可翻译基因增强疗法的反应

目的

分析两种色素性视网膜炎犬模型的 ERG 反应，一种是由于PDE6A突变，另一种是CNGB1突变，以评估这些突变对视网膜功能的影响以及基因增强疗法恢复正常功能的能力。

方法

分析了来自受 AAV 介导的基因增强治疗的年轻受影响和正常对照狗和受影响狗的暗视和明视 ERG。通过模拟 a 波的下降斜率来收集反映杆和锥功能的参数，以测量受体反应和灵敏度。通过暗视 b 波亮度-响应图的第一肢的 Naka-Rushton 拟合进一步评估棒驱动响应。

结果

PDE6A ^-/-狗表现出杆驱动反应的显着降低，杆最大反应和灵敏度非常降低。最大锥体反应的幅度略有降低。相反，CNGB1 ^-/-狗有一些残留的视杆反应，振幅和灵敏度降低，视锥细胞反应正常。基因增强治疗后，两种模型的视杆参数均得到显着改善，灵敏度参数 log S和 log K恢复，log R _max大幅增加，与治疗视网膜区域中正常视杆光转导的抢救保持一致。

结论

视杆和视锥 a 波的建模和暗视 b 波的亮度响应函数表征了两种色素性视网膜炎狗模型中视杆光感受器功能的丧失，并显示了基因增强疗法在恢复正常功能参数方面的有效性。