Abstract
Purpose :
To evaluate preclinical dose-dependent toxicity of RGX-314( AAV8-anti-VEGF Fab; Agent) delivered subretinally in the non-human primate eye.
Methods :
Adult Macaque fascicularis were used in this study. Full-field stimulation was produced with a custom made Ganzfeld stimulator controlled by a Diagnosys LLC (Lowell, MA) Espion workstation. ERGs were recorded with bipolar Burian-Allen electrodes (Hansen Labs, Coralwille, IA). The intensities of flash stimuli used (cd s m-2) were: 3 and 10 dark-adapted; 3 and 10 light-adapted. Agent was delivered at 1E10 or 1E12 vg/eye into the right eye; and left eyes served as controls. ERGs were recorded before the agent delivery, and 3, 6, 9 and 12 months after.
Results :
At the 3 month time point we obtained the following values for the ERG components [adaptation state, flash intensity in cd s m-2, component, amplitude in μV for the control eye, (standard deviation)//amplitude in μV for the injected eye, (standard deviation), p-value for a paired t-test comparing responses from the injected and control eyes]. Low dose (1E10 vg/eye, n=6): [dark, 3, a-wave, 52(18)//58 (16), 0.35]; [dark, 3, b-wave, 143(35)//152(36), 0.54]; [dark, 10, a-wave, 95(27) // 110(23), 0.23]; [dark, 10, b-wave, 162(40 //174(41), 0.38]; [light, 3, a-wave, 22(5)//19(3), 0.20]; [light, 3, b-wave, 72(15) //67(36), 0.33]; [light, 10, a-wave, 36(9)//33(7), 0.45]; [light, 10, b-wave, 73(17)//71(11), 0.63]. High dose (1E12 vg/eye, n=6): [dark, 3, a-wave, 50(23)//31 (11), 0.06]; [dark, 3, b-wave, 120(55)//78(30), 0.07]; [dark, 10, a-wave, 87(36) // 54(19), 0.04]; [dark, 10, b-wave, 133(60 //91(35), 0.02]; [light, 3, a-wave, 18(8)//10(3), 0.02]; [light, 3, b-wave, 55(24) //31(9), 0.03]; [light, 10, a-wave, 29(13)//18(7), 0.02]; [light, 10, b-wave, 55(21)//35(11), 0.04]. At the 6, 9 and 12 month time points ERGs in eyes injected with the 1E12 (high dose) were also diminished, but because of smaller numbers of animals available for these times (n=3) statistical significance was not confirmed.
Conclusions :
(1) Subretinal delivery of the RGX-314 AAV8-anti-VEGF Fab Gene at 1E10 vg/monkey eye does not produce any deficiency in retinal function detectable by full field electroretinography; (2) Statistically significant impairment of retinal function is found for the vector applications at a higher (1E12 vg/eye) dose.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.