Die Behandlung hereditärer Dystrophien und neovaskulärer Erkrankungen der Retina durch AAV-vermittelten Gentransfer

Zusammenfassung

In den vergangenen 10 Jahren wurden Strategien entwickelt, um hereditäre Dystrophien und neovaskuläre Erkrankungen der Retina durch den Transfer von Genen zu behandeln. Als optimale Genfähren (Vektoren) haben sich dabei rekombinante adenoassoziierte Viren (rAAV) etabliert. Zur Behandlung retinaler Erkrankungen werden entweder Wildtyp-Kopien der betroffenen Gene (spezifische Gentherapie) oder neuroprotektive bzw. antiangiogene Faktoren (unspezifische Gentherapie) in der Retina exprimiert. Die erfolgreiche Behandlung von RPE65^–/–-Hunden (ein natürlich auftretendes Modell für bei Menschen auftretende Netzhautdystrophien) durch spezifische Gentherapie wurde von verschiedenen Forschungsgruppen in den USA und Europa gezeigt und basierend auf diesen Studien wurden mehrere klinische Studien vorbereitet und begonnen. Um die Möglichkeit von unerwünschten Nebeneffekten durch die Gentherapie in der Retina zu minimieren, muss die Expression von neuroprotektiven bzw. antiangiogenen Faktoren regulierbar sein. Mehrere Regulationssysteme wurden schon erfolgreich in der Retina von Großtiermodellen getestet und könnten demnächst in der Klinik Anwendung finden.

Abstract

Over the last decade, significant progress has been made in the development of gene therapy strategies for the treatment of neovascular disorders and inherited dystrophies of the retina. Of all tested viral vectors, recombinant adeno-associated virus (rAAV) vectors, have been shown to be optimal vectors for gene transfer to the retina. Broadly speaking, two gene therapy strategies are used to treat retinal diseases; the first being corrective expression in the retina of the mutated gene (i. e., specific gene therapy) and the second being therapeutic expression of, for example, neurotrophic or antiangiogenic factors, in cases of neurodegenerative or neovascular, respectively, disorders (non-specific gene therapy). The naturally occurring RPE65^–/– Briard dog model has been successfully treated by specific gene transfer protocols and, based on these studies, the first clinical phase I trials are in preparation or have already begun. To avoid potential negative side effects due to the expression of neurotrophic and/or antiangiogenic factors in the retina, the expression of these transgenes needs to be regulated into a therapeutic window. Several regulatory systems have been tested in the retina of large animal models and may soon be used in clinical applications.

Schlüsselwörter

Retina - Gentherapie - erbliche Netzhauterkrankungen - AAV - neovaskuläre Erkrankungen der Retina - Regulationssysteme

Key words

retina - gene therapy - hereditary disorders of the retina - AAV - neovascular disorders of the retina - regulatory systems

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