Roughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by VEGF121 and the anti-angiogenic VEGF165b. Notably, selective inhibitors of VEGF165a, such as pegaptanib, spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects, secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF agent. Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular neovascularization, therefore a combined therapy can represent a more effective pharmacological approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment. This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into account to guide the development of novel agents targeting VEGF and/or other key factors involved in the pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms. Accordingly, this thesis also reports on novel pharmacological molecules targeting VEGF at ocular level and currently under development, with a special attention to oligonucleotide-based interventions.
Circa dieci anni fa la Food and Drug Administration (FDA) ha approvato l’uso della maggior parte dei farmaci anti-VEGF attualmente utilizzati per il trattamento della maculopatia degenerativa senile (MDS) neovascolare e altre patologie dell’occhio caratterizzate da neoangiogenesi oculare. Tuttavia, le scoperte recenti, riguardo alle attività fisiologiche delle isoforme di VEGF, impongono di riconsiderare gli effetti inibitori degli antagonisti pan-VEGF e il concetto secondo il quale risulta possibile fronteggiare le alterazioni fisiologiche a livello oculare solo attraverso il blocco completo di tutte le isoforme di VEGF. Infatti, sebbene le sostanze pan-VEGF contrastino rapidamente ed efficacemente la neovascolarizzazione oculare, la dispersione vascolare e altri cambiamenti patologici, l’inibizione di tutte le isoforme di VEGF può probabilmente comportare nel lungo termine la perdita degli effetti fisiologici esercitati da VEGF121 e dall’isoforma anti-angiogenica VEGF165b. In particolare, inibitori selettivi di VEGF165a, come per esempio Pegaptanib, risparmiano questi bersagli. Inoltre, evidenze precliniche e cliniche suggeriscono che, alla luce di queste recenti scoperte, possono essere reinterpreti anche gli effetti collaterali sistemici, secondari al trattamento intraoculare con farmaci anti-VEGF non selettivi, dando così un importante aiuto ai medici nella scelta del più appropriato trattamento anti-VEGF. Un altro aspetto da considerare è il convolgimento delle vie VEGF-indipendenti nella neovascolarizzazione oculare, dunque una terapia combinata può rappresentare un approccio farmacologico più efficace, che potrebbe aiutare anche a contrastare la tachifilassi, un’importante questione nel trattamento anti-VEGF. Questo quadro complesso e le scoperte recenti sugli attuali farmaci anti-VEGF devono essere presi in considerazione per guidare lo sviluppo di nuovi agenti che hanno come bersaglio VEGF e/o altri fattori determinanti coinvolti nella patogenesi dei disturbi neovascolari dell’occhio, lungo le vie di segnalazione stimolate dalle varie isoforme. Di conseguenza, questa tesi riporta anche nuove molecole farmacologiche aventi come target VEGF a livello oculare, e anche quelle attualmente in fase di sviluppo, con particolare attenzione agli interventi a base di oligonucleotidi.
"VEGF come target nella neovascolarizzazione oculare: terapie attuali e farmaci in fase di sviluppo."
MORO, MARIALUISA
2015/2016
Abstract
Roughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by VEGF121 and the anti-angiogenic VEGF165b. Notably, selective inhibitors of VEGF165a, such as pegaptanib, spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects, secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF agent. Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular neovascularization, therefore a combined therapy can represent a more effective pharmacological approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment. This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into account to guide the development of novel agents targeting VEGF and/or other key factors involved in the pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms. Accordingly, this thesis also reports on novel pharmacological molecules targeting VEGF at ocular level and currently under development, with a special attention to oligonucleotide-based interventions.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/18011