114 Recent Patents on DNA & Gene Sequences 2009, 3, 114-122 1872-2156/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd. Predictive Role of Gene Polymorphisms Affecting Thrombin-Generation Pathway in Variable Efficacy of Photodynamic Therapy for Neovascular Age-Related Macular Degeneration Francesco Parmeggiani, Donato Gemmati, Ciro Costagliola, Adolfo Sebastiani and Carlo Incorvaia 1 Department of Ophthalmology, University of Ferrara, Ferrara, Italy; 2 Department of Hematology, Center Study for Hemostasis and Thrombosis, University of Ferrara, Ferrara, Italy; 3 Department of Health Sciences, University of Molise, Campobasso, Italy Received: January 21, 2009; Accepted: April 2, 2009; Revised: April 18, 2009 Abstract: Age-related macular degeneration (AMD) represents the leading cause of central blindness in developed countries. The majority of severe vision loss occurs in the neovascular form of AMD, generally characterized by the presence of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) and drugs acting against vascular endothelial growth factor are the most commonly employed treatments for AMD-related subfoveal CNV. The combined use of both these strategies is the most promising therapeutic approach towards this harmful disease. The therapeutic action of PDT-V depends to a photochemical perturbation of thrombo-coagulative processes within CNV. Predictive correlations between peculiar coagulation-balance gene polymorphisms and different levels of post-PDT-V benefit have been recently documented in Caucasian patients with neovascular AMD. Particularly, heterozygous A-allele carriers of factor V Leiden 1691 or prothrombin 20210 gene are characterized by a greater possibility to exhibit clinical benefit after PDT-V. Both mutations induce thrombophilia increasing the thrombin generation in plasma and, thus, they can consistently intensify the photothrombotic phase of the therapeutic CNV occlusion. In prospect, considering the different individual susceptibility to PDT-V, a preoperative assessment of the genotypic thrombophilic background could optimize the eligibility criteria of this intriguing treatment. This review summarizes some of the recent published patents on treatment of neovascular AMD, with a particular attention to PDT-V application in combined therapeutic modalities. Keywords: Age-related macular degeneration, choroidal neovascularization, photodynamic therapy with verteporfin, single nucleotide polymorphisms, thrombin-generation pathway, thrombophilia, pharmacogenetics. I. INTRODUCTION Age-related macular degeneration (AMD) is a very common cause of central blindness or low-vision within the elders of the Western populations [1]. In particular, the most severe vision disability is secondary to neovascular form of AMD, which is frequently characterized by the subfoveal occurrence of choroidal neovascularization (CNV) [2]. AMD-related subfoveal CNV is classified according to definitions of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) and the Visudyne in Photodynamic Therapy (VIP) trials [3-8], distin- guishing four neovascular types with different fluorescein angiography (FA) patterns: i. classic CNV -a well demar- cated area of uniform hyperfluorescence surrounded by a hypofluorescent margin in the early-phase of the angio- graphy, with fluorescein leakage that obscure the boundaries through the mid- and late-phase frames; ii. predominantly classic CNV - the classic component occupying 50% or more of the area of the entire neovascular lesion (including occult CNV, blood, and other component that block the fluore- scence); iii. minimally classic CNV - the classic com- *Address correspondence to this author at the Sezione di Clinica Oculistica, Dipartimento di Discipline Medico-Chirurgiche della Comunicazione e del Comportamento, Università degli Studi di Ferrara, Corso Giovecca 203, 44100 Ferrara, Italy; Tel: (+39) 532 206338; Fax: (+39) 532 247365; E-mail: francesco.parmeggiani@unife.it ponent occupying less than 50% of the entire area of neovas- cular complex; iv. occult CNV with no classic component - including two subtypes: a) fibrovascular retinal pigment epithelium (RPE) detachment that appears as stippled hyper- fluorescence with irregular elevation of this fluorescence at the level of the RPE usually within 1-2 minutes from fluorescein injection (the boundaries are often poorly defined or difficult to demarcate and there is fluorescein leakage in the late-phase FA frames); b) poorly demarcated boundaries with fluorescein leakage from an undetermined source at the level of the RPE in the late-phase FA frames, which does not correspond to classic CNV or fibrovascular RPE detachment in the early- or mid-phase frames. At present, in patients with subfoveal CNV due to AMD, laser photocoagulation is not recommended because the eyesight would be lost for the iatrogenic damage of the overlying neurosensory photoreceptors [9, 10]. In fact, photodynamic therapy with verteporfin (PDT-V) and intravitreal injection of compounds acting against vascular endothelial growth factor (anti-VEGF) represent the most employed treatments for neovascular AMD [7, 8, 11-15]. Therapeutic effects of PDT-V are obtained by a laser- induced photothrombosis at the level of CNV, which has been previously photosensitized by the intravenous adminis- tration of verteporfin (benzoporphyrin derivative monoacid A) [16-20]. PDT-V for AMD-related CNV is worldwide