Entwicklung von cGMP-Analoga zur pharmakologischen Behandlung von neurodegenerativen Netzhauterkrankungen

Zusammenfassung

Erbliche Netzhautdegenerationen sind Erkrankungen der Photorezeptoren und/oder des Pigmentepithels, die zu einem weitgehenden Sehverlust bis hin zur vollständigen Erblindung führen. Bis heute sind diese seltenen Erkrankungen der Netzhaut zumeist nicht behandelbar und stellen eine erhebliche Belastung für die Betroffenen und ihre Angehörigen dar. Dieser Übersichtsartikel zeigt einige der Herausforderungen auf, die bei der Entwicklung von neuen Therapien für erbliche Netzhautdegenerationen auftreten, insbesondere wird auf das Problem der enormen genetischen Heterogenität dieser Erkrankungen eingegangen und die Frage, wie neue Behandlungsformen über die Blut-Netzhaut-Schranke zu den Nervenzellen der Netzhaut gebracht werden können. In diesem Rahmen wird die zentrale Rolle des Botenstoffs zyklisches Guanosinmonophosphat (cGMP) im Photorezeptor erklärt und wie dessen Funktion genutzt werden kann, um mutationsunabhängige Therapien zu entwickeln. Dies wird am Beispiel des DRUGSFORD-Projektes weiter ausgeführt, wobei auch darauf eingegangen wird, wie neue Medikamente formuliert werden können, um die Blut-Netzhaut-Schranke zu überwinden. Darüber hinaus werden weitere Schwierigkeiten diskutiert, die entstehen, wenn positive Ergebnisse aus der anwendungsbezogenen Forschung in die klinische Entwicklung überführt werden sollen. Hier wird zum einen auf Lücken und mangelnde Interdisziplinarität in der Ausbildung von Naturwissenschaftlern und Medizinern hingewiesen, zum anderen behindert aber auch das Fehlen von Verlaufsdaten und geeigneten Biomarkern die klinische Entwicklung.

Abstract

Hereditary retinal degenerative diseases are mostly diseases of the photoreceptors and/or the retinal pigment epithelium, which lead to loss of vision or even complete blindness. To this day, these diseases are mostly untreatable and represent a considerable burden for patients and their relatives. This review article highlights some of the challenges that arise in the development of new therapies for inherited retinal degeneration, in particular the problem of the enormous genetic heterogeneity of these diseases and the question of how new forms of treatment can be made to cross the blood retinal barrier to the nerve cells of the retina. In this context, the central role of the messenger substance cyclic guanosine mono-phosphate (cGMP) in the photoreceptor is discussed and how this can be used to develop mutation-independent therapies. The DRUGSFORD project will be used as an example to explain how new drugs can be formulated to overcome the blood retinal barrier. In addition, other difficulties will be discussed that arise when positive results from applied research are to be transferred into clinical development. On the one hand, gaps and a lack of interdisciplinarity in the training of scientists and physicians are pointed out; on the other hand, lack of robust data on the natural progression of these disorders and suitable biomarkers also impede clinical development.

Schlüsselwörter

cGMP - Zelltod - Apoptose - Blut-Netzhaut-Schranke

Key words

cGMP - cell death - apoptosis - blood-retinal-barrier

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