From basic to clinical research: a journey with the retina, the retinal pigment epithelium, the cornea, age‐related macular degeneration and hereditary degenerations, as seen in the rear view mirror

Abstract

. Purpose: This Acta Ophthalmologica Award and Gold Medal Honorary Lecture (the Lundsgaard Gold Medal Honorary Lecture) reviews some of the work I have carried out with my mentors and many of my wonderful collaborators and research students over more than 40 years, also including related work by other groups. It concentrates on the basic electrophysiology and ultrastructure of the retina and the retinal pigment epithelium (RPE), as well as covering basic and clinical aspects of the cornea, contact lenses, age‐related macular degeneration (AMD) and hereditary diseases. Methods: The review describes research performed using light and electron microscopy, basic and clinical electrophysiology, genetics and biochemistry in animal experiments and in research on patients. It also outlines clinically used techniques, such as laser and photodynamic treatment and scanning laser ophthalmoscopy. Results: The paper reports on the following subjects: the mechanisms behind some of the electrical potentials originating in the retina and the RPE and the use of these potentials in hereditary diseases; corneal receptors for lectins and presumably for bacteria; the turnover of the photoreceptor outer segment and the formation of lipofuscin, including the relation of these processes to AMD; certain treatments for AMD, and hereditary degenerations in animal models, such as the RPE65 gene mutation in Briard dogs, which makes them a model of Leber's congenital amaurosis. The dogs are now treated successfully with gene therapy in the USA, and a clinical trial is in preparation. Conclusions: During the last 40 years we have had the good fortune to experience a dramatic growth in knowledge and understanding within ophthalmic science of basic mechanisms. Huge progress has been made in diagnostics and clinical ophthalmological treatments, much to the benefit of our patients. Even a small contribution made by my group to these developments has been well worth the effort, particularly as scientific work is not just deeply satisfying: it is also fun!

Review of Genetics in Age Related Macular Degeneration

“…Further release of lytic enzymes and reactive oxygen damages the RPE cells, contributing to the formation of drusen. 61 One experiment that used cultured RPE cells fed with photoreceptor outer segments at two different oxygen concentrations found that cells kept in 40% oxygen accumulated two times more lipofuscin in 3 weeks than those kept at 8%. 62 This experiment demonstrates that oxidative reactions are implicated in lipofuscin formation.…”

“…This membrane thickens with age. 61 The outer segment discs form as invaginations at the base of the cells and they move to the tip of the outer segment. The RPE phagocytizes the outer segment tips daily.…”

Διερεύνηση Της Ποιότητας Ζωής Ασθενών Με Παθήσεις Της Ωχράς Κηλίδας

“…Η μεμβράνη του Bruch έχει διττό ρόλο, αφενός λειτουργεί σαν ηθμός κατά την ανταλλαγή αερίων, θρεπτικών συστατικών και μεταβολικών αποβλήτων αφετέρου παίζει στηρικτικό ρόλο για τις ανώτερες στιβάδες κυττάρων. Οποιαδήποτε διαταραχή του μελάγχρου επιθηλίου και της μεμβράνης του Bruch, όπως για παράδειγμα η πάχυνση της τελευταίας με το γήρας, μπορεί να οδηγήσει σε συσσώρευση μεταβολικών αποβλήτων και κυτταρικών υπολειμμάτων, ανάμεσα στον RPE και στην μεμβράνη του Bruch συνεισφέροντας στον σχηματισμό των drusen [76]. Σε μοριακό επίπεδο, οι βιολογικές διεργασίες που πυροδοτούν την διαταραχή της λειτουργίας των ανωτέρω δομών του αμφιβληστροειδούς, οδηγώντας στην εμφάνιση της AMD, μόλις έχουν αρχίσει να ταυτοποιούνται.…”