Genetic Biomarkers for the Response to Anti-VEGF (Vascular Endothelial Growth Factor).Treatment in Wet Age-related Macular Degeneration (Wet ARMD)

Age-Related Macular Degeneration (ARMD) is the most common cause of blindness in the adult population of the Western World. It affects the macula - the region of the retina most rich in photoreceptors and responsible for central vision.

Despite this manifest importance, the ethiology of ARMD remains poorly understood. Population-based studies have demonstrated a complex ethiology, with contributions from a combination of genetic and environmental factors. Genome-wide association studies revealed the presence of loci associated with susceptibility in a wide range of genes, including genes involved in the complement system, cholesterol homeostasis, growth factor diffusion and angiogenesis. Smoking has been identified as a major environmental factor.

Two major forms of ARMD are clinically distinguishable: the dry and wet form. The latter represents the more aggressive clinical subgroup, and is characterized by the abnormal growth of new blood vessels (neovascularization) under the macula, thus leading to the accumulation of fluid under the retina, bleeding, progression to fibrosis, and finally loss of central vision.

The pathogenesis of this neovascularization is not fully understood, although the VEGF pathway is well known to be involved in angiogenesis and was implicated in the development of the new vessels under the macula. The VEGFs are the most specific and potent stimulators of the angiogenesis. VEGF-A is a 45kD glycoprotein binding to transmembrane tyrosine kinase receptors, VEGFRs, which activates a cascade of downstream factors. VEGF-A has the strongest pro-angiogenic effect in the retina by promoting proliferation, sprouting and tubing of the endothelial cells. It can bind to at least two receptors -VEGFR1 and VEGFR2, although the most of the proangiogenic activity appears to be mediated through VEGFR2. Expression of a VEGFR2 isoform that lacks both the intracellular signaling domain and the transmembrane domain, represents a soluble form of the receptor, inactivating VEGF extracellularly.

Similarly, molecules that bind and inactivate the VEGF have been developed for the treatment of ARMD and they are applied in ARMD clinic through intra vitreal injections. These include antibodies, a recombinant receptor fusion protein and a synthetic aptamer. The anti-VEGFA antibodies - ranibizumab and bevacizumab, off-label, have been associated with limited side-effects and significant therapeutic improvement, and became the standard in the treatment of the wet form of ARMD. Indeed, for example in the first clinical trials for ranibizumab, monthly injections of ranibizumab demonstrated an average gain in visual acuity of 6.6 and 10.7 ETDRS letters after 24 months. However, currently most clinical centres apply modified treatment protocols. Commonly used is an initial loading dose of three consecutive monthly injections and subsequent follow-up and administration of additional injections depending on the evolution of visual acuity, optical coherence tomography and fluorescein angiography data . 25% of the ARMD patients show significant improvement of the visual acuity, 70% maintain or show slightly increased visual acuity, and the remaining 5 percent of the patients fail to respond to the treatment and continue to loose vision.

The difference seen in response to anti VEGF treatment for ARMD between the patients is suggestive for the presence of factors influencing the effect of the drug. Some of these could be genetic variants within genes involved in ARMD pathogenesis or VEGF pathway. Few associations with markers within genes previously found to be related with the pathogenesis of ARMD have been found. It remains unknown whether variants involved in the anti VEGF treatment response could influence the therapeutic outcome.

A study demonstrated that the single nucleotide polymorphism (SNP) in VEGFR1 rs7993418 (TAC codon) form is associated to resistance to the anti VEGF therapy in carcinoma patients. This specific genotype leads to an increased expression of the VEGFR1 without changing the amino acid content of the protein. The increased VEGFR1 protein is most likely due to higher efficiency of messenger ribonucleic acid (mRNA) translation.

The purpose of this trial is to evaluate the association between a panel of selected polymorphic markers in the VEGF pathway and the response to therapy with anti VEGF antibody for ARMD. The hypothesis is that the individual genotype influences the response to the anti VEGF. This can lead to identification of genetic biomarkers allowing treatment individualization and optimization of the visual outcomes.