June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Schlemm canal-targeted Tie2 knockdown (SC-Tie2 KD) as mouse model of adult-onset human glaucoma
Author Affiliations & Notes
  • Alejandra Bosco
    Neurobiology, University of Utah Health, University of Utah Health, Salt Lake City, UT, US, academic/health, Salt Lake City, Utah, United States
  • Cesar O Romero
    Neurobiology, University of Utah Health, University of Utah Health, Salt Lake City, UT, US, academic/health, Salt Lake City, Utah, United States
  • Joon Schwakopf
    Neurobiology, University of Utah Health, University of Utah Health, Salt Lake City, UT, US, academic/health, Salt Lake City, Utah, United States
  • Oleg Yarishkin
    Salk Institute for Biological Studies, La Jolla, California, United States
  • J Cameron Millar
    North Texas Eye Research Institute, University of North Texas, Fort Worth, Texas, United States
  • Michael Steele
    Neurobiology, University of Utah Health, University of Utah Health, Salt Lake City, UT, US, academic/health, Salt Lake City, Utah, United States
  • David Krizaj
    Ophthalmology and Visual Sciences, University of Utah Health, Salt Lake City, Utah, United States
  • Monica L Vetter
    Neurobiology, University of Utah Health, University of Utah Health, Salt Lake City, UT, US, academic/health, Salt Lake City, Utah, United States
  • Footnotes
    Commercial Relationships   Alejandra Bosco None; Cesar Romero None; Joon Schwakopf None; Oleg Yarishkin None; J Cameron Millar None; Michael Steele None; David Krizaj None; Monica Vetter None
  • Footnotes
    Support  NEI Grant 1R21EY033131-01; BrightFocus Foundation/National Glaucoma Research Grant G2019219; University of Utah Neuroscience Initiative Path to Program Grant 2019.
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1848. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Alejandra Bosco, Cesar O Romero, Joon Schwakopf, Oleg Yarishkin, J Cameron Millar, Michael Steele, David Krizaj, Monica L Vetter; Schlemm canal-targeted Tie2 knockdown (SC-Tie2 KD) as mouse model of adult-onset human glaucoma. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1848.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Angiopoietin-Tie2/TEK signaling at the Schlemm's canal (SC) critically regulates aqueous humor outflow (AHO) and intraocular pressure (IOP) in humans and mice. Tie2 receptor loss-of-function mutations associate with primary congenital and open angle glaucoma (POAG), and conditional Tie2 knockout adult mice show SC regression, chronic IOP elevation and glaucomatous degeneration. However, systemic Tie2 deletion reduces choriocapillary flow, causing cone photoreceptor loss. To avoid potential effects on retinal/choroidal or systemic endothelial Tie2, we developed a targeted approach to selectively attenuate Tie2 expression in the SC of adult mice, and report their glaucomatous pathology.

Methods : Adeno-associated virus AAV2, which transduces rodent SC, was used to deliver Cre recombinase (AAV2-Cre) by bi- or unilateral injection into the anterior chamber of Tie2 FL/FL C57BL/6 mice aged 1-1.5 months. Live, we measured in AAV2-Cre vs. AAV2-GFP and naive littermates: weekly IOP (n>20 eyes/group) for 8 to 12 weeks post-injection (wpi), AHO facility 4 wpi (n=6-11 eyes), optomotor reflex and pSTR (n=5-13 mice), and retina/optic nerve head integrity by optic coherence tomography (OCT; n=7 mice) 12 wpi. Postmortem, we analyzed: AAV2 transduction 2-8 wpi (n=3-5 mice), and density of optic nerve axons and retinal ganglion cells immunostained for RBPMS and Brn3a 12 wpi (n=6-13 mice).

Results : AAV2-Cre selectively transduced the SC endothelium, leading to impaired AHO facility 4 wpi, and to significant IOP elevation from 1-4 wpi that persisted to 8 or 12 wpi. Visual acuity and pSTR amplitude were significantly decreased in AAV2-Cre eyes 12 wpi, relative to the controls, whereas ERG a- and b-waves were unaffected. OCT showed intact outer retinal layers, but significant thinning of the inner retina and optic nerve head 12 wpi. RGC analysis showed significant RBPMS+ RGC loss with maximal degeneration localized to the dorsal retina, and significant RGC decline (Brn3a-) preceding loss 12 wpi. Optic nerve analysis detected significant axon density drop, coupled to RGC loss, 12 wpi.

Conclusions : The "SC-Tie2 knockdown" model reproduces a pathogenic mechanism of humans POAG, undergoing chronic ocular hypertension, and progressive glaucomatous optic neuropathy and retinopathy. This model thus offers a robust and reproducible model of POAG, valuable for advancing its treatment.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×