July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Safety of the Subretinal Delivery of RGX-314 AAV8-anti-VEGF Fab Gene Therapy in NHP: Retinal Structure Over One Year
Author Affiliations & Notes
  • Michael J. Ammar
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Elaine J Zhou
    Perelman School of Medicine, University of Pennsylvania , Philadelphia , Pennsylvania, United States
  • Jessica Ijams Wolfing Morgan
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Katherine E Uyhazi
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Arkady Lyubarsky
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Erik Wielechowski
    Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gui-Shuang Ying
    Center for Preventative Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Erin Bote
    Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Leah Makaron
    Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Stephen Yoo
    REGENEXBIO, Rockville, Maryland, United States
  • James Wilson
    Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Jean Bennett
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Albert M Maguire
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Anna Tretiakova
    Pfizer, Inc, RDRU, Cambridge, Massachusetts, United States
  • Tomas S Aleman
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Michael Ammar, None; Elaine Zhou, None; Jessica Morgan, None; Katherine Uyhazi, None; Arkady Lyubarsky, None; Erik Wielechowski, None; Gui-Shuang Ying, None; Erin Bote, None; Leah Makaron, None; Stephen Yoo, 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 US Patent 7282199; US 8962332; US 7790449 (P); Jean Bennett, None; Albert Maguire, None; Anna Tretiakova, None; Tomas Aleman, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1422. doi:
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      Michael J. Ammar, Elaine J Zhou, Jessica Ijams Wolfing Morgan, Katherine E Uyhazi, Arkady Lyubarsky, Erik Wielechowski, Gui-Shuang Ying, Erin Bote, Leah Makaron, Stephen Yoo, James Wilson, Jean Bennett, Albert M Maguire, Anna Tretiakova, Tomas S Aleman; Safety of the Subretinal Delivery of RGX-314 AAV8-anti-VEGF Fab Gene Therapy in NHP: Retinal Structure Over One Year. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1422.

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

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Abstract

Purpose : To evaluate the long-term (one year) safety and define an upper dose limit of subretinally delivered RGX-314 AAV8-anti-VEGF Fab as a treatment for wet AMD in non-human primates (NHP).

Methods : Cynomolgus monkeys, ages 3-5 years, received a single, unilateral, subretinal injection of 1e10 (‘low’, n=6), 1e12 (‘high’, n=6) AAV8 GC/eye, or of a vehicle-control (n=4). The contralateral eye served as an uninjected control. Retinal structure was evaluated with spectral domain optical coherence tomography (SD-OCT) at 3 months post-injection; a subset of these animals (high-dose, n=2; low-dose, n=3; injected-control, n=2) were evaluated every 3 months for 12 months post-injection. Overlapping SD-OCT scans were performed to ensure coverage of the treated retina. SD-OCT cross-sections within injected regions were co-registered to baseline cross-sections. The thickness of the total retina (TRT), inner retina (IRT), and outer nuclear layer (ONL) within injected regions were compared to the same retinal locations pre-injection.

Results : Retinal demelanization separated the injected regions from uninjected retina in all injected (including vehicle-injected) eyes from the earliest visit and remained unchanged in extent over time. There were no signs of intraocular inflammation. No significant SD-OCT changes were observed in vehicle-injected compared to uninjected eyes (99 percentile limits for change: TRT=14%, IRT= 31%, ONL=18%) at 3 months, or during the 12-month follow-up. Eyes injected with the low-dose vector showed no significant differences during the entire observation period in TRT, IRT or ONL thickness compared to baseline values. Four of six eyes from the high-dose vector group showed significant ONL thinning within the injected regions at 3 months accompanied by non-significant thickening of the inner retina. One of two animals of the high-dose group who were followed for 12 months had normal ONL thickness at 3 months but showed ONL progressive thinning over time.

Conclusions : Subretinal injections of AAV8-anti-VEGF Fab in NHP demonstrated long-term safety in the low dose group with no apparent changes on main SD-OCT structural parameters out to 12 months and notable structural changes in the high dose group in the area of injection. Findings from this study support the long-term safety of the low dose and help establish the upper dose limit for future RGX-314 clinical trials.

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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