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Retinal Neovascularization: More Veg, less VegF

  November, 8 2005 23:32
your information resource in human molecular genetics
Diabetic retinopathy and wet age-related macular degeneration together cause the majority of progressive blindness in the world today with millions over the age of 65 presenting these diseases in the US alone. Both diseases present as pathologies of the retina involving the induction of new aggressive blood vessel growth leading to edema and macular thickening. This can lead to rapid loss of vision and eventual scarring of the retinal tissues and bleeding in the eye. This scar tissue and blood produces a dark, distorted area in the vision, often rendering the eye legally blind.

In wet age-related macular degeneration, the choroidal capillary bed institutes angiogenesis that leads to blood vessel growth erupting through the retinal layers and leaking blood. This edematous pathology leads to a thickening of the central vision region; the macular, which in turn leads to loss of vision.

The growth and maintenance of blood vessels is a complex process involving manifold signaling pathways. Initial endothelial cell division, migration and maturation of the new vessels is mediated, in part, by vascular endothelial growth factor (VegF) a protein factor that comes at least six flavors. The main player has been identified as Vegf 165 (the splice variant containing 165 amino acids). This protein has thus been the target of many drug development efforts centered on the loss of VegF functional effect.

Macugen (Pegaptanib, Eyetech) is the only FDA approved anti-VegF pharmacological therapy currently available for the treatment of wet age-related macular degeneration. The active ingredient is a DNA aptamer that is designed to bind to the Vegf 165 isoform. Studies have shown that this drug can slow, and in some cases, halt the progression of vision loss.

Another therapy in late-stage development is Lucentis (Ranibizumab, Genentech), an antibody fragment designed against all six isoforms of VegF. Clinical trials with this drug have reported that some patients actually gain vision compared to base line at study entry. In the most recent Phase III news, the ANCHOR trial (the latest in a nautically titled series: MARINA, SAILOR…) showed that 96% of wet AMD patients maintained or improved vision – a result that confirms previous data and finalises the BLA for FDA filing in December. Interestingly, the parent molecule for Lucentis, Avastin (Bevacizumab, Genentech), previously thought too large to pass through the upper retinal layers for efficacy, has shown significant efficacy in off-label use for AMD. The benefit for patients with Avastin, a drug approved for metastatic colorectal cancer, is that administration can be intravenous. Macugen and Lucentis both require intravitreal injection; a needle in the eye. Development of Avastin for retinal disease in at an earlier stage than Lucentis but it is hoped that FDA approval will be soon.

Other pharmacological interventions targeting VegF include siRNA from Acuity Pharmaceuticals and Sirna therapeutics. Both therapies target different parts of the VegF signaling pathway. Sirna-027 (Sirna) targets the mRNA for the VegF receptor VEGFR1; in this way attenuating the signal for new vessel growth by silencing expression of the receptor. Cand5 (Acuity) targets the VegF mRNA, thereby reducing the expression of VegF protein. The ophthalmic space awaits their trial data with enthusiasm.

A second prong attacking retinal disease centers on the clear benefit of a high-vegetable diet. Several recent studies have indicated a strong link between nutrition and the development of macular degeneration. It has been demonstrated that people with diets high in fruits and vegetables (especially leafy green vegetables) have a lower incidence of macular degeneration. Free radicals generated by sunlight, cigarette smoke, air pollution, infection, and metabolism can cause damage to the retinal layers and direct the induction of neovascularization. Dark green, leafy vegetables contain two pigments, lutein and zeaxanthin, which accumulate in the eye. These two appear to be able to snuff out free radicals before they can harm the eye's sensitive tissues. The AREDS trial confirmed the beneficial effect of vitamin supplements and zinc (antioxidants)on the progression age-related disease.

The current research in retinal disease encompasses molecular biological approaches as well as nutritional control and highlights the cross-functional effort being brought to bear on these indications. Hum-molgen will continue to track development in this exciting and fast moving field of ophthalmology.

Message posted by: Simon Chandler

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