April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Dose-Related Gene Silencing of RTP801 With the siRNA PF04523655 in Long Evans Rat Models of STZ Induced Diabetes and Laser Induced CNV
Author Affiliations & Notes
  • K. D. Rittenhouse
    Translational Medicine Ophthalmology, Pfizer Inc, San Diego, California
  • B. Hirakawa
    Translational Medicine Ophthalmology, Pfizer Inc, San Diego, California
  • W. Huang
    Translational Medicine Ophthalmology, Pfizer Inc, San Diego, California
  • A. S. Basile
    Translational Medicine Ophthalmology, Pfizer Inc, San Diego, California
  • T. Johnson
    Translational Medicine Ophthalmology, Pfizer Inc, San Diego, California
  • R. Schachar
    Translational Medicine Ophthalmology, Pfizer Inc, San Diego, California
  • Footnotes
    Commercial Relationships  K.D. Rittenhouse, Pfizer Inc., E; B. Hirakawa, Pfizer Inc., E; W. Huang, Pfizer Inc., E; A.S. Basile, Pfizer Inc., E; T. Johnson, Pfizer Inc., E; R. Schachar, Pfizer Inc., E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 6447. doi:
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      K. D. Rittenhouse, B. Hirakawa, W. Huang, A. S. Basile, T. Johnson, R. Schachar; Dose-Related Gene Silencing of RTP801 With the siRNA PF04523655 in Long Evans Rat Models of STZ Induced Diabetes and Laser Induced CNV. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6447.

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

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Abstract

Introduction: : RTP801 is a hypoxia-induced stress response gene implicated in retinopathy. PF-04523655 (PF-655) is a 19-mer siRNA targeting the RTP801 gene. PF-655 is currently in Phase II clinical trials for wet AMD and DME.

Purpose: : To characterize the dose-response profile of PF-655 in rodent STZ-induced diabetes and rodent laser induced CNV models following intravitreous (IVT) administration.

Methods: : 1. Rats (n=12 per group) were administered IV STZ. Following sacrifice (day 8, 15, 22, 29), retina and RPE/choroid were collected and analyzed using qPCR. 2: STZ-treated rats (n=12 per group) received PF-655 (10 ug/eye IVT) after onset of diabetes (day 14). Following sacrifice (day 15, 22, 29, 43), retina and RPE/choroid were collected and analyzed using qPCR. 3: Rats (n=12 per group) received 4-6 laser burns using 810 nm diode laser disrupting Bruch’s membrane. Immediately after laser and on day 8, both eyes of rats received IVT PF-655 (1, 2.5, 50 ug/eye) or saline (n=8 per group). Fluorescein angiograms were taken on day 15 and CNV lesions were rated for severity (n = 4 per group). Animals were then sacrificed and retina and RPE/choroid tissues collected and analyzed using qPCR.

Results: : STZ Model - RTP801 mRNA was upregulated in RPE/choroid (~70%, p<0.05 day 29) in diabetic rats relative to normal controls. PF-655 administration (10 ug/eye): (A) Retina RTP801 expression was reduced ~40% relative to STZ control one day after PF-655 IVT and reached the levels similar to STZ control by 14 days post-dose. (B) RPE/choroid RTP801 expression was reduced ~65% relative to STZ control one day after IVT PF-655 and remained below STZ control levels up to 14 days post-dose. CNV Model: (A) Dose-related silencing of RTP801 mRNA was observed in retina. Maximal silencing (~50%) was detected at the 50 ug/eye dose level (p <0.05). (B) PF-655 treatment resulted in a mean reduction (~50%) in the percent of eyes with grade 3 or 4 lesions relative to control.

Conclusions: : The siRNA, PF-655 silences RTP801 expression in animal models of AMD and DME.

Keywords: gene/expression • diabetic retinopathy • age-related macular degeneration 
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