Format

Send to

Choose Destination
Invest Ophthalmol Vis Sci. 2014 Mar 4;55(3):1232-40. doi: 10.1167/iovs.13-13449.

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

Author information

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

Abstract

PURPOSE:

The intraocular pharmacodynamics of PF-04523655, a small-interfering RNA (siRNA) directed against RTP801, was characterized using rat models of retinopathy.

METHODS:

Rat models of streptozotocin-induced diabetes and wet AMD were used to determine the onset, extent, and duration of siRNA inhibition of retinal RTP801 expression by PF-04523655, and this inhibition was characterized by pharmacokinetic/pharmacodynamic (PK/PD) modeling. A rat model of wet AMD was also used to examine PF-04523655 dose-dependent effects on the incidence of clinical grade 3 or 4 choroidal neovascularization lesions. Whole homogenate versus laser-capture microdissected (LCM) retinal samples were analyzed by quantitative PCR for RTP801 expression.

RESULTS:

RTP801 expression in RPE/choroid (RPE/C) increased in diabetic rats by up to 70% above nondiabetic rat levels. Inhibition of retinal RTP801 expression by PF-04523655 began 1 day after intravitreous injection and was observed through day 7 in the neurosensory retina and through day 14 or longer in RPE/C. PF-04523655 inhibition of RTP801 expression was maintained well after clearance of PF-04523655 from the eye and was best characterized by an effect compartment PK/PD model. Moreover, PF-04523655 administration decreased the incidence of clinical grade 3 or 4 lesions by approximately 60% (P = 0.053), and dose-dependently inhibited retinal RTP801 expression (P < 0.01). RTP801 expression was enriched in the outer nuclear layer in LCM samples.

CONCLUSIONS:

In rodent retinopathy models, administration of the siRNA, PF-04523655, reduced RTP801 expression in the retina, consistent with the RNA-induced silencing complex (RISC) mechanism of action. The pharmacodynamic profile from the animal models could be useful to elucidate dose and exposure dependency of RTP801 expression inhibition by siRNA.

KEYWORDS:

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

PMID:
24458146
DOI:
10.1167/iovs.13-13449
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center