May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
SYL04003: A New Therapeutic Candidate for Treating Ocular Hypertension Using RNAi Technology
Author Affiliations & Notes
  • A. Jimenez
    R & D, Sylentis, Colmenar Viejo Madrid, Spain
  • A. Sesto
    R & D, Sylentis, Colmenar Viejo Madrid, Spain
  • J. Pintor
    Bioquímica y Biología Molecular IV,
    Universidad Complutense, Esc. Optica, Madrid, Spain
  • A. Mediero
    Bioquímica y Biología Molecular IV,
    Universidad Complutense, Esc. Optica, Madrid, Spain
  • P. Loma
    Bioquímica y Biología Molecular IV,
    Universidad Complutense, Esc. Optica, Madrid, Spain
  • A. Peral
    Optica II,
    Universidad Complutense, Esc. Optica, Madrid, Spain
  • Footnotes
    Commercial Relationships  A. Jimenez, Sylentis, E; A. Sesto, Sylentis, E; J. Pintor, None; A. Mediero, None; P. Loma, None; A. Peral, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1643. doi:https://doi.org/
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      A. Jimenez, A. Sesto, J. Pintor, A. Mediero, P. Loma, A. Peral; SYL04003: A New Therapeutic Candidate for Treating Ocular Hypertension Using RNAi Technology. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1643. doi: https://doi.org/.

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

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Abstract

Purpose: : Finding a new treatment for ocular hypertension and open angle glaucoma studying Carbonic anhydrase IV (CAIV) specific siRNA involved in intraocular pressure (IOP) regulation.

Methods: : Different CAIV siRNA sequences, previously validated by in vitro assays, were tested in vivo in New Zealand rabbits to analyze the effect on IOP levels.siRNAs were administered as eyedrops in saline solution (0.9% w/v). Different experiments were performed in order to obtain data concerning: maximal IOP reduction, longest-lasting time effect, long term treatments, dose-response studies, administration pattern, analysis of in vivo downregulation, and preliminary toxicology studies. As controls for in vivo studies, both commercial drugs and scrambled siRNAs, were analyzed.

Results: : The CAIV-specific siRNA caused a decrease in IOP of 14.47±5% lasting 72 hours. The commercial drug Xalatan, used as a control, reduced IOP 23.40 ± 2.36 % lasting 5 to 6 hours. The IOP decreases obtained by instillation of CAIV-specific siRNA in rabbits were maintained during one month of treatment with a daily dose with no rebound effect. No side-effects were observed after or during one month of treatment. Dose-response studies allowed to obtain the EC50 value and the administration pattern studies suggested that consecutive doses are the most effective treatment. The in vivo analysis of CAIV gene expression showed a clear reduction of mRNA levels in the ciliary body of treated animals. On the other hand, the preliminary toxicology experiments performed in rabbit and mouse showed no toxicological effects after CAIV-specific siRNA administration.

Conclusions: : These results postulate SYL04003 as a new therapeutic candidate to treat ocular hypertension and open angle glaucoma. The IOP decrease obtained with CAIV-specific siRNAs is similar to that produced by commercial drugs, but siRNA treatment shows a generalized long lasting effect when compared to commercials. The preliminary results also indicated that the long term treatment maintained the IOP reduction and no toxicological effects were observed.

Keywords: carbonic anhydrase • anterior chamber • ciliary body 
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