July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Safety of subretinal delivery of RGX-314 (AAV8-anti-VEGF Fab) in the non-human primate as assessed by full-field ERG
Author Affiliations & Notes
  • Arkady Lyubarsky
    Center for Advanced Retinal and Ophthalmic Therapies (CAROT); FM Kirby Center for Mol Ophthal, SOM Univ. of Pennsylvania, Philadelphia, Pennsylvania, United States
    Vision Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Erik Wielechowski
    Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Tomas S Aleman
    Scheie Eye Institute, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Albert M Maguire
    Center for Advanced Retinal and Ophthalmic Therapies (CAROT); FM Kirby Center for Mol Ophthal, SOM Univ. of Pennsylvania, Philadelphia, Pennsylvania, United States
    Scheie Eye Institute, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Gui-Shuang Ying
    Scheie Eye Institute, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Erin Bote
    Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Leah Makaron
    Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Jessica Ijams Wolfing Morgan
    Scheie Eye Institute, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Anna Tretiakova
    Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • James Wilson
    Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Jean Bennett
    Center for Advanced Retinal and Ophthalmic Therapies (CAROT); FM Kirby Center for Mol Ophthal, SOM Univ. of Pennsylvania, Philadelphia, Pennsylvania, United States
    Scheie Eye Institute, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Arkady Lyubarsky, None; Erik Wielechowski, None; Tomas Aleman, None; Albert Maguire, REGENEXBIO (F), Spark Therapeutics (F); Gui-Shuang Ying, None; Erin Bote, None; Leah Makaron, None; Jessica Morgan, None; Anna Tretiakova, None; James Wilson, REGENEXBIO (F), REGENEXBIO (I), REGENEXBIO (C), REGENEXBIO (P), Solid Gene Therapy (C), Ultragenyx Gene Therapy (F), Ultragenyx Gene Therapy (C), University of Pennsylvania (P); Jean Bennett, Biogen (F), Gensight Biologics (C), Gensight Biologics (R), Gensight Biologics (S), Limelight (F), REGENEXBIO (F), Sanofi (C), Spark Therapeutics (C), Spark Therapeutics (R), Spark Therapeutics (S)
  • Footnotes
    Support  REGENXBIO, University of Pennsylvania Center for Advanced Retinal and Ophthalmic Therapeutics (CAROT), NIH P30 EY001583
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4546. doi:
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      Arkady Lyubarsky, Erik Wielechowski, Tomas S Aleman, Albert M Maguire, Gui-Shuang Ying, Erin Bote, Leah Makaron, Jessica Ijams Wolfing Morgan, Anna Tretiakova, James Wilson, Jean Bennett; Safety of subretinal delivery of RGX-314 (AAV8-anti-VEGF Fab) in the non-human primate as assessed by full-field ERG. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4546.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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