June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Development of a RNAi therapeutic for the treatment of allergic conjunctivitis
Author Affiliations & Notes
  • Ana Isabel Jimenez
    R&D, Sylentis, Madrid, Spain
  • Tamara Martinez
    R&D, Sylentis, Madrid, Spain
  • Victoria Gonzalez
    Preclinical, Sylentis, Madrid, Spain
  • Carmen Martinez-Garcia
    Universidad de Valladolid, Valladolid, Spain
  • Covadonga Paneda
    R&D, Sylentis, Madrid, Spain
  • Footnotes
    Commercial Relationships Ana Isabel Jimenez, Sylentis (E); Tamara Martinez, Sylentis (E); Victoria Gonzalez, Sylentis (E); Carmen Martinez-Garcia, Sylentis (F); Covadonga Paneda, Sylentis (E)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4883. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Ana Isabel Jimenez, Tamara Martinez, Victoria Gonzalez, Carmen Martinez-Garcia, Covadonga Paneda; Development of a RNAi therapeutic for the treatment of allergic conjunctivitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4883.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: We have shown that Orai1, the pore forming subunit of the CRAC calcium channel, is upregulated in ovoalbumin-induced allergic conjunctivitis in mice. Down-regulation of Orai1 has been shown to reduce sneezing and nasal rubbing in animal models of allergic rhinitis. We have designed a battery of siRNA to silence Orai1 and selected the most efficacious product for further development for the treatment of allergic conjunctivitis.

Methods: The efficacy of different siRNAs to down-regulate Orai as well as their effect on cell survival was assessed in human and murine cell lines. In vivo efficacy of the lead compound and chemically stabilized versions was studied in a mouse model of ovoalbumin-induced allergic conjunctivitis.

Results: SYL116011 was shown to be the most potent of the sequences studied, causing a maximal reduction of Orai1 mRNA levels of 80% in human cells and 70% in mouse cells. This reduction was observed in absence of alteration of cell viability. Prophylactic SYL116011 treatment of a mouse model of ovoalbumin-induced ocular allergy caused a dose dependent-reduction of allergy related clinical signs (chemosis and tearing) and a reduction in the infiltration of mast cells and eosinophils in the conjunctiva; these observations were equivalent to those observed in response to patanol and to some extent better than those observed in response to levocabastine. The reduction in clinical signs and cell infiltration correlated with a reduction in the expression levels of allergy biomarkers in the mouse eye (TLSP and CD137).

Conclusions: We have identified a compound that efficiently down-regulates Orai1. Prophylactic treatment of allergic mice with this compound causes a reduction in allergy related endpoints. <br />

×
×

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.

×