June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Four-year follow up of intraocular pressure (IOP) control in a canine model of open-angle glaucoma (OAG) treated with adeno-associated virus (AAV)-mediated modification of gene expression within the aqueous humor outflow pathways (AHOP)
Author Affiliations & Notes
  • Andras M Komaromy
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Christine Harman
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Kristin Koehl
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Amanda Anderson
    Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, United States
  • Sanford L Boye
    Department of Pediatrics and the Powell Gene Therapy Center, University of Florida, Gainesville, Florida, United States
  • Juan Pedro Steibel
    Department of Animal Science & Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan, United States
  • Leandro Teixeira
    Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Carol B Toris
    Ophthalmology & Visual Sciences, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, United States
    Ophthalmology and Visual Sciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • Sayoko E Moroi
    Ophthalmology and Visual Sciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
  • Shannon E Boye
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Andras Komaromy, CRISPR Therapeutics (F), PolyActiva Pty Ltd (F); Christine Harman, None; Kristin Koehl, None; Amanda Anderson, None; Sanford Boye, Atsena Therapeutics (F), Atsena Therapeutics (C), Atsena Therapeutics (R); Juan Pedro Steibel, None; Leandro Teixeira, None; Carol Toris, None; Sayoko Moroi, Wolters Kluwer Health (R); Shannon Boye, Atsena Therapeutics (F), Atsena Therapeutics (C), Atsena Therapeutics (R)
  • Footnotes
    Support  NIH R01-EY025752, R01-EY024280, P30-EY007003, MSU Discretionary Funding Initiative (DFI), Glaucoma Research Foundation, Research to Prevent Blindness, Foundation Fighting Blindness, Edward Sheppard and family.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2783. doi:
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    • Get Citation

      Andras M Komaromy, Christine Harman, Kristin Koehl, Amanda Anderson, Sanford L Boye, Juan Pedro Steibel, Leandro Teixeira, Carol B Toris, Sayoko E Moroi, Shannon E Boye; Four-year follow up of intraocular pressure (IOP) control in a canine model of open-angle glaucoma (OAG) treated with adeno-associated virus (AAV)-mediated modification of gene expression within the aqueous humor outflow pathways (AHOP). Invest. Ophthalmol. Vis. Sci. 2021;62(8):2783.

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

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Abstract

Purpose : To demonstrate that gene enhancement therapy of the AHOP following a single intracameral AAV injection results in long-term stable IOP control by preventing extracellular plaque formation in the trabecular meshwork (TM) of a well-established canine OAG model.

Methods : Six 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). Clinical outcome measures were monitored for 24-48 months, including weekly diurnal IOP, repeated aqueous humor (AH) flow measurements, and high-resolution imaging of retina and optic nerve head (ONH) by optical coherence tomography (OCT). IOP analysis consisted of pairwise comparisons of treated vs. fellow control eyes while accounting for dog-to-dog variation. Safety monitoring included routine clinical ophthalmic examinations and AH analyses (protein concentrations, cell counts, and neutralizing AAV antibody titers). Ocular tissues were examined by routine light and transmission electron microscopy (TEM).

Results : IOP decreased significantly and was less variable for the entire 24- to 48-month observation period in 5/6 ADAMTS10-mutant dogs in treated vs. fellow control eyes (16.6±7.5 vs. 29.7±8.7 mmHg; p<0.0001). Outflow facility was significantly higher and more variable in treated (0.34±0.15) vs. untreated (0.23±0.08) eyes (p<0.01). OCT imaging showed that ONH morphology remained unchanged over time in successfully treated eyes, but degeneration/cupping progressed in untreated controls. Mild anterior uveitis with positive neutralizing antibody titers developed in the serum of all dogs as well as in the AH of AAV-treated but not untreated fellow eyes. TEM examination of the TM revealed almost complete prevention of extracellular plaque formation in treated vs. untreated eyes.

Conclusions : Long-term, stable IOP control can be achieved for at least 4 years following a single intracameral injection of AAV in a clinically relevant canine OAG model. These findings are consistent with reduced extracellular TM plaque formation and increased AH outflow facility.

This is a 2021 ARVO Annual Meeting abstract.

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