June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Subretinal delivery of RGX-314 AAV8-anti-VEGF Fab gene therapy in NHP
Author Affiliations & Notes
  • Anna Tretiakova
    Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Tomas S Aleman
    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
  • Elaine J Zhou
    Perelman School of Medicine, 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
    REGENXBIO, Rockville, Maryland, United States
  • Jean Bennett
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Albert M Maguire
    Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
    Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • James Wilson
    Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Anna Tretiakova, None; Tomas Aleman, None; Arkady Lyubarsky, None; Elaine Zhou, None; Erik Wielechowski, None; Gui-Shuang Ying, Chengdu Kanghong Biotech (C), Janssen Research & Development (C); Erin Bote, None; Leah Makaron, None; Stephen Yoo, REGENXBIO (E); Jean Bennett, Biogen (F), Gensight Biologics (C), Gensight Biologics (R), Gensight Biologics (S), Limelight (F), REGENXBIO (F), Sanofi (C), Spark Therapeutics (R), Spark Therapeutics (S), Spark Therapeutics (C); Albert Maguire, REGENXBIO (F), Spark Therapeutics (F); James Wilson, 7282199 (P), 7790449 (P), 8962332 (P), Dimension Therapeutics (I), Dimension Therapeutics (C), Dimension Therapeutics (F), REGENXBIO (C), REGENXBIO (F), REGENXBIO (I), Solid Gene Therapy (C)
  • Footnotes
    Support  REGENXBIO and Gene Therapy Program and Center for Advanced Retinal and Ocular Therapeutics (CAROT) at UPENN.
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4509. doi:
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      Anna Tretiakova, Tomas S Aleman, Arkady Lyubarsky, Elaine J Zhou, Erik Wielechowski, Gui-Shuang Ying, Erin Bote, Leah Makaron, Stephen Yoo, Jean Bennett, Albert M Maguire, James Wilson; Subretinal delivery of RGX-314 AAV8-anti-VEGF Fab gene therapy in NHP. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4509.

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

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Abstract

Purpose : To evaluate safety and define an upper dose limit of an anti-VEGF Fab-containing AAV8 gene therapy vector for wet age-related macular degeneration in non-human primates (NHP) following subretinal delivery.

Methods : 20 NHPs were used in the study. Animals received a single subretinal injection of 1e10 (low), 1e12 (high) AAV8 GC/eye or a control. Production of anti-VEGF Fab was assessed by VEGF ELISA of anterior chamber (AC) fluid. A separate NHP study assessed a 1e11 (middle) GC/eye dose. Retinal structure was evaluated with spectral domain optical coherence tomography (SD-OCT) imaging at 3 months. Retinal function was evaluated using full-field electroretinography (ERG). Retinal distribution of anti-VEGF Fab mRNA and protein was evaluated.

Results : At 30 days post injection, expression in control NHPs (n=4) was not detectable. Median expression in low dose NHPs (n=6) was 889 ng/ml (ranging 679 - 2116 ng/ml) and in high dose NHPs (n=6) 2452 ng/ml (ranging 966 - 3500 ng/ml). The middle 1e11 dose (n=8, separate study) showed median expression of 1505 ng/ml (ranging 431 - 2346 ng/ml). Anti-VEGF Fab mRNA and protein were distributed widely throughout the retina well beyond the injection site. Retinal demelanization was present in all injection sites, with no signs of intraocular inflammation. Low dose NHPs showed no significant difference in retinal thickness relative to vehicle controls. There was 10% decrease in total retinal thickness at injection site in high dose NHPs. 1e11 dosed NHP’s SD-OCTs are under evaluation. At 10 months, 4 eyes from 2 NHPs in 1e11 group were normal histologically; minimal perivascular infiltrates were present in one optic nerve. Histopathologic changes at 3 months in the low dose eyes included minimal inflammation in the choroid and in the high dose eyes included inflammation in the retina, choroid, and sclera. No significant changes in thicknesses were observed in the control animals. Control or low dose NHPs did not show measurable changes in retinal function. High dose resulted in a statistically significant (p<0.05) decline in the amplitude of ERG as compared to baseline, formulation control, and low dose.

Conclusions : The study demonstrated presence of anti-VEGF Fab in AC at 30 days in all RGX-314 doses and the feasibility of using OCT and ERG as structural and functional measures and to define an upper dose limit in NHP dose escalation studies.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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