Investigative Ophthalmology & Visual Science Cover Image for Volume 65, Issue 7
June 2024
Volume 65, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2024
Longitudinal BLamD quantification analyses reveal a critical window for disease pathophysiology in R345W EFEMP1 mice
Author Affiliations & Notes
  • Antonio Ortega
    Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • John Hulleman
    Ophthalmology and Visual Neurosciences, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Footnotes
    Commercial Relationships   Antonio Ortega None; John Hulleman None
  • Footnotes
    Support  The Edward N. and Della L. Thome Memorial Foundation Award in AMD Research, R01-EY027785, Larson Endowed Chair for Macular Degeneration Research (UMN)
Investigative Ophthalmology & Visual Science June 2024, Vol.65, 4752. doi:
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    • Get Citation

      Antonio Ortega, John Hulleman; Longitudinal BLamD quantification analyses reveal a critical window for disease pathophysiology in R345W EFEMP1 mice. Invest. Ophthalmol. Vis. Sci. 2024;65(7):4752.

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

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Abstract

Purpose : Similarly to humans, mice spontaneously form basal laminar deposits (BLamDs) with age. In R345W Efemp1 mice (a model of Doyne Honeycomb Retinal Dystrophy), the presence of these deposits are greatly exacerbated and serve as the main tangible ocular phenotype in this early AMD-like model. We hypothesize that by systematically quantifying BLamDs across different ages in these mice we could gain insight into the pathogenesis of BlamDs, discover critical ages for treatment interventions, and create timelines of disease progression.

Methods : R345W+/+ Efemp1 and WT cohorts were aged to 4, 8, 12, and 16 mo (3M/3F per group). Additionally, Nlrp3-/-R345W+/+ and Casp1-/-R345W+/+ mice were also aged to 16 mo (previously noted reduced BLamDs at younger ages). Electron micrographs were obtained from processed samples every 6 fields of view (FOV) at 2,500x mag along the Bruch’s membrane (20 FOV/eye). BLamDs were traced and quantified using ImageJ, compiled, and then subjected to comparison using Brown-Forsythe and Welch ANOVA tests.

Results : Both R345W+/+ Efemp1 and WT mice exhibited similar timelines of disease progression with no significant increase of BLamDs quantified from 4 to 8 mo (p= 0.2483, p=>0.999), followed by an onset of rapid progression and growth from 8 to 12 mo (p= 0.0005, p= 0.0329), then plateauing from 12 to16 mo (p= 0.9998, p= 0.8038). R345W+/+ mice demonstrated a 1.5-fold increase in BLamDs growth from 8 to 12 mos. At 16 mos, R345W+/+ mice had a 1.5-fold greater average accumulation of BLamDs than WT (2.96 v. 7.92 µm2/FOV) (p= <0.0001). At this age, both Casp1-/- and Nlrp3-/- ameliorated the R345W+/+ phenotype by significantly protecting against BLamD progression (p= 0.0012, p= 0.0073), and maintaining WT-like BLamD growth (p= 0.0618, p= 0.1551).

Conclusions : Our data creates a timeline for disease progression of both spontaneous and R345W+/+ induced BLamDs. By quantifying BLamDs across aged cohorts, we uncovered a window for potential treatment interventions for this early AMD-like disease pathology. This window begins at 8 mo in R345W+/+ mice with the onset of BLamDs at which we can begin to administer targeted preventative treatments. It concludes at 12 months where the exacerbated growth of BLamDs plateaus. This timepoint can serve as an endpoint for treatment, or, more excitingly, a point at which to begin treatments for the reversal of BLamD pathophenomenon.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

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