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RTP801 gene expression is differentially upregulated in retinopathy and is silenced by PF-04523655, a 19-Mer siRNA

Kay D Rittenhouse1, Theodore R Johnson, Paolo Vicini

  • 1Ophthalmology External Research Unit, External R&D Innovations, Pfizer, Inc., San Diego, California.

Investigative Ophthalmology & Visual Science
|January 25, 2014
PubMed
Summary

PF-04523655, a small-interfering RNA (siRNA), effectively reduced RTP801 expression in rat retinopathy models. This inhibition, lasting up to 14 days, suggests potential therapeutic applications for retinal diseases.

Keywords:
gene expression, PK/PD, hypoxia, retinal pigment epithelium, retinal ischemia

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Area of Science:

  • Ophthalmology
  • Molecular Biology
  • Pharmacology

Background:

  • Retinopathy, including diabetic retinopathy and wet age-related macular degeneration (AMD), involves complex molecular pathways.
  • RTP801 expression is implicated in the pathogenesis of certain retinal diseases.
  • Small-interfering RNA (siRNA) technology offers a targeted approach to modulate gene expression.

Purpose of the Study:

  • To characterize the intraocular pharmacodynamics of PF-04523655, an siRNA targeting RTP801.
  • To evaluate the efficacy of PF-04523655 in inhibiting RTP801 expression in rodent models of retinopathy.

Main Methods:

  • Utilized rat models of streptozotocin-induced diabetes and wet AMD.
  • Determined the onset, extent, and duration of siRNA-mediated RTP801 inhibition using quantitative PCR on retinal samples.
  • Employed pharmacokinetic/pharmacodynamic (PK/PD) modeling to characterize the inhibition.
  • Assessed the effect of PF-04523655 on choroidal neovascularization (CNV) incidence.

Main Results:

  • RTP801 expression increased significantly in diabetic rat retinas.
  • PF-04523655 initiated RTP801 inhibition within 1 day, lasting up to 14 days or longer in the RPE/choroid.
  • Inhibition persisted after drug clearance, consistent with an effect compartment PK/PD model.
  • PF-04523655 reduced severe CNV lesions by approximately 60% and dose-dependently inhibited RTP801 expression.

Conclusions:

  • PF-04523655 effectively reduced retinal RTP801 expression in rodent retinopathy models.
  • The observed inhibition aligns with the RNA-induced silencing complex (RISC) mechanism.
  • The pharmacodynamic profile supports further investigation into dose and exposure dependency for siRNA-based therapies.