July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Long-term stable intraocular pressure (IOP) control and optic nerve head (ONH) preservation following AAV-mediated ocular gene therapy in a canine model of ADAMTS10-open-angle glaucoma (OAG)
Author Affiliations & Notes
  • Andras M Komaromy
    Small Animal Clinical Studies, Michigan State Univ, Coll of Vet Med, East Lansing, Michigan, United States
  • Kristin L Koehl
    Small Animal Clinical Studies, Michigan State Univ, Coll of Vet Med, East Lansing, Michigan, United States
  • Christine Harman
    Small Animal Clinical Studies, Michigan State Univ, Coll of Vet Med, East Lansing, Michigan, United States
  • Sanford L Boye
    Pediatrics, University of Florida, Gainesville, Florida, United States
  • Juan P. Steibel
    Animal Science & Fisheries and Wildlife, Michigan State University, Michigan, United States
  • Leandro B C Teixeira
    Pathobiological Sciences, University of Wisconsin, Wisconsin, United States
  • Carol B Toris
    Ophthalmology and Visual Sciences, Case Western Reserve University, Ohio, United States
  • Sayoko Eileen Moroi
    Ophthalmology and Visual Sciences, University of Michigan, Michigan, United States
  • Shannon Elizabeth Boye
    Ophthalmology, University of Florida, New York, United States
  • Footnotes
    Commercial Relationships   Andras Komaromy, None; Kristin Koehl, None; Christine Harman, None; Sanford Boye, None; Juan Steibel, None; Leandro Teixeira, None; Carol Toris, None; Sayoko Moroi, None; Shannon Boye, None
  • Footnotes
    Support  NIH R01-EY025752, R01-EY024280, P30-EY007003, MSU Discretionary Funding Initiative (DFI), Research to Prevent Blindness, Foundation Fighting Blindness, Edward Sheppard and family.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6470. doi:
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      Andras M Komaromy, Kristin L Koehl, Christine Harman, Sanford L Boye, Juan P. Steibel, Leandro B C Teixeira, Carol B Toris, Sayoko Eileen Moroi, Shannon Elizabeth Boye; Long-term stable intraocular pressure (IOP) control and optic nerve head (ONH) preservation following AAV-mediated ocular gene therapy in a canine model of ADAMTS10-open-angle glaucoma (OAG). Invest. Ophthalmol. Vis. Sci. 2019;60(9):6470.

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

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Abstract

Purpose : To achieve long-term, stable IOP control by AAV-mediated gene replacement therapy in the aqueous humor outflow pathways (AHOP) of a well-established canine OAG model with a mutation in ADAMTS10.

Methods : One wildtype (wt) and 6 ADAMTS10-mutant dogs with early stages of OAG were injected unilaterally with a 75-100μL volume of single stranded AAV2(Y444F)-smCBA-hADAMTS10 vector (1.25-1.61 x 1012 vector genomes). Eyes were treated with topical difluprednate ophthalmic emulsion and antibiotic. Clinical outcome measures were monitored for 12-24 months, including weekly diurnal IOP, repeated aqueous humor (AH) flow measurements, and high-resolution imaging of retina and ONH by optical coherence tomography. IOPs analysis consisted of LOESS curve fitting with Bonferroni’s adjustment. Safety monitoring included AH protein concentrations, cell counts, neutralizing AAV antibody (nAb) titers, and histopathology.

Results : IOP decreased significantly and was less variable for 12 (n=2) to 24 (n=2) months in 4/6 ADAMTS10-mutant dogs in treated vs. fellow control eyes (13.9±1.8 vs. 28.6±4.2 mmHg; p<0.01). In the wt dog, mean IOPs were 9.1±0.9 vs. 18.4±1.6 mmHg in treated vs. untreated eye over 12 months (p<0.0001). Conventional outflow facility was significantly higher and more variable in treated (0.35±0.15) vs. untreated (0.24±0.9) eyes (p<0.01). ONH morphology remained unchanged in successfully treated eyes, but degeneration/cupping progressed in untreated controls. Regarding safety, mild anterior uveitis with positive AH nAb titers developed in all AAV-treated eyes. Inflammation was controlled as confirmed by AH sample analyses and histopathology.

Conclusions : In an OAG large animal model, we provide proof-of-concept that long-term IOP control and ONH protection is achieved by targeting transgene expression to the AHOP with a single stranded AAV2-based vector. Based on the outcome measures of conventional outflow facilities and stable, low IOPs, we speculate that both conventional and unconventional AHOP may have been targeted – a notion supported by our pilot reporter gene expression studies. Low IOP in the treated wt eye suggests a potential nonspecific therapeutic effect of ADAMTS10 overexpression within the AHOP.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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