July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Subconjunctival dendrimer-cyclosporin therapy for the treatment of dry eye in a rabbit model of induced autoimmune dacryoadenitis
Author Affiliations & Notes
  • Hui Lin
    Wilmer Eye Institute, Johns Hopkins University, Lutherville Timonium, Maryland, United States
  • Rishi Sharma
    Wilmer Eye Institute, Johns Hopkins University, Lutherville Timonium, Maryland, United States
  • Siva Pramodh Kambhampati
    Wilmer Eye Institute, Johns Hopkins University, Lutherville Timonium, Maryland, United States
  • Kannan Rangaramanujam
    Wilmer Eye Institute, Johns Hopkins University, Lutherville Timonium, Maryland, United States
  • Samuel C Yiu
    Wilmer Eye Institute, Johns Hopkins University, Lutherville Timonium, Maryland, United States
  • Footnotes
    Commercial Relationships   Hui Lin, None; Rishi Sharma, None; Siva Kambhampati, None; Kannan Rangaramanujam, None; Samuel Yiu, None
  • Footnotes
    Support  Supported in part by an unrestricted grant from Research to Prevent Blindness, New York, NY, to the Wilmer Eye Institute, and NIH/NEI R01 1R01EY025304-01 (RMK).
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 299. doi:
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      Hui Lin, Rishi Sharma, Siva Pramodh Kambhampati, Kannan Rangaramanujam, Samuel C Yiu; Subconjunctival dendrimer-cyclosporin therapy for the treatment of dry eye in a rabbit model of induced autoimmune dacryoadenitis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):299.

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

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Abstract

Purpose : The inflammation of ocular surface and lacrimal gland (LG) has been identified in dry eye and plays a role in the pathogenesis. Our previous study showed subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and dendrimer- dexamethasone suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in a rabbit model of induced autoimmune dacryoadenitis (AID). In this study, we aim to evaluate the efficacy of the single subconjunctival injection of dendrimer delivered cyclosporin (CSA) in the treatment of dry eye in the AID model.

Methods : Dendrimer-CsA conjugate was constructed by using a combination of highly efficient copper(I) catalyzed alkyne-azide (CuAAC) click chemistry, thiol-ene click and Steglich reactions, and HPLC was performed. Diseased animals were treated with Restasis eyedrops twice a day, dendrimer-CSA (D-CSA), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer’s test, tear breakup time (TBUT), and fluorescein and rose Bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR.

Results : All the intermediates and the final conjugate was extensively characterized using 1H-NMR, 13C-NMR, HPLC and MALDI-TOF MS analyses. The release of the free drug shown as CsA peaks through cleavable ester linkage. At two weeks post single dose-treatment, the D-CSA and Restasis group showed improved clinical evaluations. H&E staining demonstrated less inflammatory cell infiltration and fewer atrophic acini in D-CSA group, compared to those treated with saline or Restasis. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-CSA group than in other treatment groups. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-CSA group and the Restasis when compared to saline group.

Conclusions : Single subconjunctivally administered D-CSA suppressed LG inflammation at least to a comparable level as twice daily Restasis treatment, leading to partial recovery of LG function with clinical improvement in induced AID. Sjögren’s patients may benefit from this targeted nanomedicine approach.

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

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