July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
αB crystallin peptide fused to elastin-like polypeptide provides long-term neuroprotection in a mouse model of AMD
Author Affiliations & Notes
  • Parameswaran G Sreekumar
    Ophthalmology, Doheny Eye Institute, Los Angeles, California, United States
  • Zhe Li
    Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
  • Wan Wang
    Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
  • Christine Spee
    USC Roski Eye Institute, University of Southern California, Los Angeles, California, United States
  • J. Andrew MacKay
    Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
    USC Roski Eye Institute, University of Southern California, Los Angeles, California, United States
  • David R Hinton
    Pathology, University of Southern California, Los Angeles, California, United States
    USC Roski Eye Institute, University of Southern California, Los Angeles, California, United States
  • Ram Kannan
    Ophthalmology, Doheny Eye Institute, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Parameswaran Sreekumar, None; Zhe Li, None; Wan Wang, None; Christine Spee, None; J. Andrew MacKay, None; David Hinton, None; Ram Kannan, None
  • Footnotes
    Support  EY01545, the Whittier foundation, the Gavin S. Herbert Endowed Chair of Pharmaceutical Sciences,and the Arnold and Mabel Beckman Foundation.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2457. doi:
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    • Get Citation

      Parameswaran G Sreekumar, Zhe Li, Wan Wang, Christine Spee, J. Andrew MacKay, David R Hinton, Ram Kannan; αB crystallin peptide fused to elastin-like polypeptide provides long-term neuroprotection in a mouse model of AMD. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2457.

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

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Abstract

Purpose : Administration of NaIO3 to mice causes marked retinal pigment epithelium (RPE) damage and retinal degeneration on day 7. A single intravitreal injection of αB crystallin peptide fused to elastin-like polypeptide (crySI) significantly inhibited retinal degeneration compared to a free 20-mer αB crystallin mini-peptide (mini cry) (Sreekumar et al. ARVO 2017). Herein, we report the long-term protective effect of crySI in the NaIO3 mouse model as well as protection of human polarized RPE monolayers.

Methods : Ten male 129S6/SvEvTac mice (4-8 weeks old) were used per group.

See scheme at end of abstract.

Intra-ocular disposition of crySI and mini cry were compared by color fundus images after intravitreal injection of fluorescein-labeled substrates. Polarized human RPE monolayers were cotreated in apical and basal cellular compartments with NaIO3 and either mini cry, SI or crySI for 24h. Transepithelial resistance (TER) of RPE monolayers was measured and cells were labeled for ZO1.

Results : Eyes challenged with NaIO3 had large areas of retinal degeneration (>50%) compared to controls. In contrast, challenged mice pre-treated from 7 to 14 days with a single intra-vitreal injection of crySI had significantly lower retinal degeneration (<25%) compared to mice treated with the mini cry. H&E staining revealed major tissue disruption in all control NaIO3 challenged mice; however, only crySI consistently protected against this disruption. The retention of crySI was prolonged (6 weeks) in the vitreous when compared to mini cry that was cleared within two days, which confirms that ELP-mediated assembly of crySI increases exposure to the retina. In vitro studies in polarized RPE monolayers showed that 2.5 mM NaIO3 significantly reduced TER and caused disruptions in tight junction protein ZO-1; furthermore, crySI (10 µM) maintained TER similar to controls confirming a protective role for crySI.

Conclusions : Intra-vitreal injection of crySI attenuates NaIO3 induced retinal degeneration in mice by rescuing RPE and preventing disruption of other retinal layers. crySI has potential as a treatment for AMD since the ELP fusion results in long-term (at least 6 weeks) retention thereby offering extended retinal protection.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

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