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As I have mentioned ad nauseum in this column recently, the spate of interest in ocular neo-vascularization inhibition, and its application to devastating retinal disease, shows no signs of slowing. A case in point is highlighted in the latest issue of Gene Therapy. Shen and coworkers, following the work with Macugen and Avastin/Lucentis, once again target the VEGF signaling cascade; a prime mover in the process of angiogenesis. This time, the authors use a modified siRNA to digest the mRNA encoding the VEGFR-1 (flt-1) receptor. Previous work has demonstrated that this receptor can act as a decoy for VEGF-A, reducing its active concentration and acting as a brake on vascularization and hyperpermeability. In other scenarios, however, VEGFR-1 has shown proangiogenic activity, probably through the binding of placental growth factor (PLGF) – VEGFR-1 specific ligand.
The siRNA was modified by the addition of inverted abasic moieties at both the 5’ and 3’ ends of the sense strand, and a single phosphorothioate linkage between the last two nucleotides at the 3’ end of the antisense strand. These modifications significantly increase the stability of the molecule in the vitreous and ocular tissue.
After proving selectivity for VEGFR-1 over VEGFR-2, in both human aortic endothelial cells and in HeLa cells using a luciferase fusion, the authors applied two mouse models to show efficacy. The first model; a laser-induced rupture of Bruch’s membrane leading to choroidal neovascularisation (a wetAMD mimic) showed a severe reduction in VEGFR-1 mRNA 7 days post treatment with the single intravitreal injection of SIRNA-027 (anti-VEGFR-1 siRNA). This clear activity was then tested in mice with oxygen-induced ischemic retinopathy (a diabetic retinopathy model. In this more controlled study, the authors treated only one eye, with the contralateral eye being an appropriate untreated comparator. Again the result showed a clear reduction in VEGFR-1 mRNA (57% from a single 3ug dose).
Careful analysis of retinal cross-sections after BrdU-labelled SIRNA-027 administration determined that the siRNA was localized to the retinal ganglionic cells, the inner nuclear layer as well as the inner limiting membrane, proving that the siRNA can access all layers of the retinal tissue. Using the laser –induced CNV model, the authors tested the siRNA as an inhibitor of neovascularisation. Fourteen days after rupture of Bruch’s membrane, eyes receiving Sirna-027 showed remarkably smaller areas of CNV in comparison to an inverted control RNAi. Even when the route of administration was changed to tissues surrounding the eye, a clear therapeutic effect was evident. This result was borne-out in the ischemic retinal model; a model that induces neovascularisation by a very different route and mimicks more the etiology of diabetic retinopathy. In summary, then, this exciting work shows a novel class of therapeutic compounds, based on the RNAi mechanism, that have a clear functional activity in the pathological angiogenic diseases of the retina. These compounds may provide ophthalmologists with a new armamentarium to combat retinal disease.
Message posted by: Simon Chandler
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