Universitäts-Augenklinik Tübingen
Department für Augenheilkunde

(gefördert durch die Kerstan Stiftung)
Es ist bekannt, dass auch die innere Netzhaut bei Retinitis pigmentosa über die Jahre teilweise degeneriert. Die verbliebene Funktionalität der inneren Netzhaut ist auch nach Erblindung bei den Betroffenen interindividuell unterschiedlich. Das Projekt möchte untersuchen, ob die Degeneration bei betroffenen Patienten auch die höhere Sehbahn betrifft und inwiefern die morphologischen und funktionellen Veränderungen der Sehrinde etwaige Versuche das Sehen wiederherzustellen limitieren können.

Es gibt Hinweise darauf, dass die unterschiedliche Zellen der menschlichen Netzhaut (Zapfen, Stäbchen, ON/OFF-Bipolarzellen, Ganglienzellen) durch unterschiedliche elektrische Frequenzen spezifisch stimuliert werden können. Durch einen neuen Versuchsaufbau für die transkorneale Elektrostimulation können verschiedene Frequenzen transkorneal appliziert werden. Dadurch wird die Aktivität bestimmter retinaler Neurone manipuliert, die wiederrum (dem Stromverlauf entsprechend) abwechselnd eine Konstriktion und erneute Erweiterung der Pupille auslösen. Diese „elektrisch-evozierten Pupillenreflexe“ werden parallel von einer Infrarotkamera aufgezeichnet. Gewisse Merkmale der Pupillenantwort sollen Aufschluss über die Sensitivität der Neurone für die jeweilige Stimulationsfrequenz geben. Mit Hilfe von seltenen Krankheitsmodellen können wir beim Menschen herausfinden, ob Stäbchen, Zapfen, Bipolarzellen und Ganglienzellen spezifisch  elektrisch angesprochen werden können.

Die normalerweise für die Versorgung der Retina zuständigen Zellen (vor allem das RPE) haben sich der jahrelangen reduzierten Funktion der Photorezeptoren angepasst. Die plötzliche Reaktivierung der Stäbchen durch die Gentherapie löst nun ein metabolisches und energetisches Ungleichgewicht aus.
Transkorneale Elektrostimulation (TES) könnte die anfängliche Reaktivierung und das Nachwachsen von äußeren Stäbchensegmenten erleichtern und die Anpassung an die erhöhte Energieanforderung in der Netzhaut von RP-Patienten nach einer Gentherapie fördern.

Transcorneal Electrical Stimulation (TES) using the Okustim device is a non-invasive, CE-approved treatment for patients with retinitis pigmentosa (RP). Studies suggest TES can slow retinal degeneration and improve visual function, likely through neuroprotective mechanisms, anti-inflammatory effects, and possible improvements in retinal blood flow. Current commercial devices use a standardized 20 Hz stimulation frequency, based on early perceptual threshold studies. However, recent research indicates different retinal cells respond preferentially to distinct frequency bands, with photoreceptors being most sensitive to low frequencies and inner retinal neurons to higher frequencies. This opens the possibility of tailoring TES to specific cellular responses for greater therapeutic benefit.

This exploratory project investigates how varying TES parameters affect retinal function and metabolism in patients with retinitis pigmentosa caused by USH2A gene mutations. Using specialized ophthalmological examinations, the study aims to monitor neuroprotective and functional outcomes under different stimulation conditions. While not intended for regulatory approval, the findings could provide new insights into TES mechanisms and inform future improvements in therapy effectiveness.

This project investigates whether transcorneal electrical stimulation (TES) can enhance outcomes and reduce complications following gene therapy with voretigene neparvovec in patients with RPE65-linked retinitis pigmentosa. Although gene therapy can restore visual function, some patients develop rapid postoperative retinal atrophy, likely caused by an imbalance in retinal energy metabolism when dormant rods are suddenly reactivated. The study proposes that TES, known for its neuroprotective and metabolic effects, may help stabilize the retina during this critical adjustment period.

The specific aims are twofold: (1) to test whether repeated TES can improve the functional rescue of the retinal network after gene supplementation, and (2) to evaluate whether TES can prevent or reduce the formation of postoperative atrophy by supporting photoreceptor survival and helping the retina adapt to higher energy demands, TES may prolong and strengthen the benefits of gene therapy. Beyond voretigene neparvovec, the findings could also inform future therapeutic strategies for other photoreceptor-related diseases.

Aufgrund des langsamen und individuellen Krankheitsverlaufs sind herkömmliche diagnostische Verfahren für die Evaluation therapeutischer Effekte begrenzt geeignet. Aus diesem Grund bekommen sogenannte Biomarker eine immer höhere Bedeutung um kleinstmögliche Veränderungen frühestmöglich detektieren zu können. Die Fluoreszenz von Flavoproteinen (FPF), als nicht-invasive Bildgebungsmethode, besitzt ein großes Potenzial als sensitiver Biomarker, welcher funktionellen und morphologischen Schäden vorausgeht.

Siehe auch

Im Rahmen der Studie soll die longitudinale Analyse der individuellen Progressionsraten bei Morbus Stargardt Patienten die klinische Interpretation des FPF-Werts und dessen Eignung als neuer Biomarker bei Morbus Stargardt ermöglichen. Hierfür werden im Verlauf über zwei Jahre bei 30 Patienten multimodale Untersuchungen der retinalen Funktion, Morphologie und des retinalen Stoffwechsels evaluiert.

Is an observational study that applies a novel clinical examination protocol that integrates multimodal assessments of retinal structure, function, and metabolism. By combining these complementary approaches, the project aims to generate a comprehensive understanding of retinal alterations in retinitis pigmentosa caused by mutations in PDE6A, PDE6B, and RHO.

More specifically, the study aims to investigate how metabolic, morphological, and functional aspects of the retina correlate in affected patients. Additionally, to evaluate the variability and reproducibility of the applied methods, examinations are performed at two separate time points. The knowledge gained will contribute to optimizing assessment protocols for future interventional clinical trials, improving the evaluation of safety and efficacy in potential treatment approaches.

Our research focuses on understanding how inherited retinal diseases, such as retinitis pigmentosa (RP), affect not only the retina but also the broader visual system. While RP has long been considered primarily a disorder of photoreceptor degeneration, recent evidence suggests that structural and functional changes extend beyond these cells, involving inner retinal layers, and potentially central visual pathway structures in the brain. By studying these complex remodeling processes, we aim to gain a deeper understanding of how vision loss progresses and how different cellular and neural systems interact in the course of disease.

Our work is dedicated to exploring how retinal disorders influence vision at multiple levels, including the central nervous system, by combining advanced imaging methods with clinical routine examinations to identify reliable biomarkers that support diagnosis, monitor disease progression, and assess therapeutic outcomes.

This project aims to establish a robust European multicenter retrospective and prospective dataset to characterize the natural history of PROM1-associated IRDs. Stratification by inheritance pattern, genotype and geographic origin will enable insights into variant distribution and potential genotype-phenotype correlations, thereby contributing to the translational readiness of PROM1 as a therapeutic target. The project addresses essential diagnostic and safety considerations that will become increasingly relevant as gene therapy for PROM1-associated IRDs approaches clinical application. These include the separate assessment of cone and rod function, the use of objective functional diagnostics (e.g., electroretinography or pupillography) and wavelength-specific methods like color perimetry for reliable cone sensitivity evaluation. Particular emphasis will be placed on comprehensive rod function testing, using methods capable of assessing the scotopic sensitivity range, which has been insufficiently considered in prior gene therapy studies. By addressing functional, diagnostic and metabolic aspects, this project aims to establish a clinical diagnostic framework to guide future therapeutic strategies, patient counseling and post-treatment monitoring in PROM1-associated IRDs.

The full-field electroretinography (ERG) records the summed electrical responses of the retina to light stimuli, providing insight into the functional integrity of different retinal layers. Among its main components, the oscillatory potentials (OPs) are fast wavelets (75–300 Hz) that appear between the a- and b-waves. They are thought to originate from inner retinal circuitry involving bipolar, amacrine, and ganglion cells, and are particularly sensitive to changes in retinal physiology.

Traditionally, OPs are analysed by filtering the ERG signal to isolate high-frequency components and evaluating their amplitude and timing. However, this approach limits the ability to observe how these oscillations evolve over time. To overcome this, time-frequency methods such as continuous wavelet transform (CWT) have been introduced. The CWT enables the simultaneous examination of temporal and spectral characteristics, providing a more comprehensive description of the OPs’ dynamic behaviour. This approach allows for a refined characterisation of retinal activity and enhances sensitivity to subtle functional alterations, offering valuable insights into both normal and pathological retinal processing.

Electroretinography (ERG) has been a routine diagnostic tool in ophthalmology in the last 50 years. It has gained an important role in identification of mainly photoreceptor diseases. Nevertheless, with coming forward of new treatment options, the clinical questions changed and moved away from pure diagnostic identification of diseases. In our research we explore new protocols for ERG and test how they could be used in the role of clinical trials biomarkers, especially for interventional clinical trials for photoreceptor diseases (retinal dystrophies). The main focus is to develop testing strategies allowing testing in an environment without an optimal signal to noise ratio, such as retinal degeneration. Specifically, a better evaluation of the noise level in comparison to the signal would allow better signal measurements. Our focus lies also on flicker stimuli with work designed to test specific flicker parameters involved in cone-rod interactions. Besides the classical testing strategy with simple stimuli, we are also testing complex stimulus paradigms in order to address interactions between different retinal pathways and to optimize retinal responses according to these positive or negative interactions.

Standard automatic perimetry can measure retinal disease severity but cannot distinguish between rods, long/middle-wavelength (L/M)–sensitive, and short-wavelength (S)–sensitive cones. Considering new generation of interventional approaches in clinical trials designed to have specific effect on photoreceptors, there is a demand to provide perimetrical redouts specifically sensitive for individual types of photoreceptors. More specialized devices like dark adapted perimetry have the ability to identify the rod contribution but also fail to separate between L/M or S sensitive cones. Therefore, a new type of commercial perimeter (MonCV1) was used to develop clinical protocols specifically sensitive for individual type of photoreceptors inside the Perimetry consortium for IRD (PERIRD). The next goal is to test these protocols in different retinal diseases and build criteria necessary to define new biomarkers related to perimetric testing in clinical trials of retinal dystrophies.

Flavoprotein fluorescence (FPF) imaging is a method to monitor cellular mitochondrial stress by measuring concentration of flavoproteins. Briefly, by monitoring the intensity of green emitted lights after excitation with blue light, it is possible to evaluate an accumulation of oxidized flavoproteins, which reflects the oxidative stress and mitochondrial dysfunction. Since the introduction of commercially available device OcuMet Beacon (OcuSciences, Ann Arbor, MI, USA), this imaging has been applied to various retinal diseases, including diabetic retinopathy, age-related macular degeneration or central serous retinopathy. In his project we try to understand the effect of mitochondrial stress to the progression of retinal degeneration and to test how this biomarker could be used to evaluate neuroprotective interventions developed in clinical therapy. In that context we test healthy retinas for the re-test variability and for daily life factors influences on the values, as well as the influence of dark-adaptation. In the next phase, factors related to mitochondrial DNA polymorphisms will be evaluated. The goal of this project is to understand and introduce new sets of measurements specifically tailored to address metabolic changes in the retina introduced not only in inherited retinal degenerations, but also normal aging or more common eye diseases like age-related macular degeneration or glaucoma.

The current clinical diagnostics in retinal diseases is driven by evaluation of structural, functional or metabolic tests. However, this testing is generated by several different devices and is not automatically integrated in a common viewer of multidimensional diagnostic. Our current project tries to fill this gap and its main goal is to allow an easy integration of functional, structural and metabolic retinal tests. By enabling such a multimodal evaluation, the retinal evaluation does not depend on a single modality, but allows a much more complex interpretation of the findings. The ultimate goal is therefore establishing a new generation of interconnected biomarkers for diagnostic and prognostic evaluation of retinal diseases, especially in specific retinal dystrophies. The additional goal is also then to establish a new set of biomarkers designed as specifically tailored readouts for clinical trials.

The process of dark adaptation is a complex change of photoreceptor sensitivity in dark-adaptation after light exposure. In this project we try to establish new protocols for using this test as evaluation of retinal metabolic capacity at specific retinal location. In contrast to standardized protocols, we wish to use protocols with lower light intensity which could be much easier tolerated by patients with retinal diseases. The current project is testing reliability of these new protocols in the healthy subjects and in groups of specifically selected retinal dystrophies.

Chromatic pupil campimetry (CPC) allows measuring the local retinal function objectively by analyzing the pupil response to local perimetric stimuli. Moreover, by using specially designed photoreceptor specific stimulus and applying gaze tracking, we are able to introduce a functional retinotopic examination regardless of fixation problems specifically targeting retinal function of interest. Thus, CPC dose allow an objective monitoring of disease progression, rendering it as a biomarker for novel treatments. Although electroretinography is a widely established objective retinal examination, its ability to measure reproducible signals is very limited in disease state. This, CPC being the only available objective local retinal functional examination in situations with reduced retinal cells number such as retinal degeneration, it became a crucial part of the clinical routine in our site. Nevertheless, the current setup is only used in our institution. Therefore, the main goal of this project is to build a new generation of CPC devices with free to use setup, which would allow an easy transfer of this methodology to other specialized medical and scientific institutions. Additionally, the current project will use knowledge accumulated in last ten years to optimize and improve CPC. By increasing the recording speed of the camera and optimizing pupil detection algorithm we will try to further increase the stability and measurement precision. Also, by implementation of new projection monitors we do wish to further increase possible spectra of stimulus characteristics with special focus of introducing different type of frequency modulation, allowing better and more substantial characterization of retinal responses.