Therapie des diabetischen Makulaödems mit den VEGF-Inhibitoren Ranibizumab und Bevacizumab: Schlüsse aus grundlegenden In-vitro-Untersuchungen

Zusammenfassung

Die diabetische Retinopathie (DR) mit Ausbildung eines diabetischen Makulaödems (DME) ist eine häufige und ernste, den Visus bedrohende Erkrankung. Da bei vielen Patienten eine Laserbehandlung des DME nicht zu einer Visusverbesserung führt, ist die Verbesserung der Prognose der DME-Patienten durch eine medikamentöse Therapie ein wichtiges Ziel der ophthalmologischen Forschung. Hemmung des Wachstumsfaktors „vascular endothelial growth factor“ (VEGF) zur Therapie des DME erscheint mechanistisch plausibel, da der bei DR verstärkt im Auge vorkommende VEGF die Permeabilität von Endothelzellschranken wesentlich beeinflusst. Diese Wirkung des VEGF ist im Vergleich zur angiogenen Wirkung durch Stimulation von Proliferation und Migration der retinalen Endothelzellen bisher allerdings weniger gut untersucht. Von In-vitro-Untersuchungen an primären und immortalisierten retinalen Endothelzellen kann abgeleitet werden, dass VEGF tatsächlich eine Schlüsselrolle bei der Regulation der retinalen Endothelzellschranke spielt. Selbst in Gegenwart einer Reihe anderer bei DR verstärkt vorkommender Wachstumsfaktoren, kann durch die in klinisch erreichbaren Konzentrationen eingesetzten VEGF-Inhibitoren Ranibizumab (Lucentis®) und Bevacizumab (Avastin®) eine schnelle Normalisierung erreicht werden. Im Gegensatz zu dem Antikörperfragment Ranibizumab akkumuliert der komplette Antikörper Bevacizumab bei längerer Exposition sowohl in retinalen Endothelzellen als auch in Pigmentepithelzellen. Diese Beobachtung erscheint interessant im Hinblick auf eine Behandlung von Patienten mit VEGF-Hemmern über viele Jahre, bei der bisher noch unerkannte Nebenwirkungen einer Langzeittherapie auftreten könnten.

Abstract

Diabetic macular oedema (DMO) which may occur at all stages of diabetic retinopathy (DR) is a severe vision-threatening complication. In most cases, laser treatment does not improve visual acuity. Therefore research in ophthalmology focuses on the improvement of the prognosis of DMO patients with a drug-based DMO therapy. Vascular endothelial growth factor (VEGF) is considered the most important therapeutic target because this growth factor also is the most potent permeability factor affecting the inner retinal barrier formed by endothelial cells (ECs). Compared to its angiogenic stimulation of proliferation and migration of ECs, effects of VEGF on permeability have not been studied in all details. In vitro investigations on the behaviour of primary or immortalised retinal endothelial cells confirmed the key role of VEGF in the regulation of the permeability of the inner retinal barrier. Despite the presence of a variety of other factors found to be elevated in DR, a VEGF-disrupted barrier can be completely restored with the VEGF-inhibiting ranibizumab (Lucentis®) and bevacizumab (Avastin®) when applied at clinically achievable concentrations. The antibody bevacizumab, but not the antibody fragment ranibizumab, accumulates in both retinal EC and pigment epithelial cells during prolonged treatment. This observation might be relevant because patients are often treated for several years and additional long-term side effects may be recognised in the future.

Schlüsselwörter

VEGF - Ranibizumab - Bevacizumab - diabetisches Makulaödem - In-vitro-Studien - Retina

Key words

VEGF - ranibizumab - bevacizumab - diabetic macular edema - in vitro studies - Retina

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