M Dominik Fischer

M Dominik Fischer
Universitätsklinikum Tübingen · Eye Hospital

Professor of Ophthalmology

About

113
Publications
15,990
Reads
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2,309
Citations
Additional affiliations
September 2015 - present
University of Oxford
Position
  • Honorary Clinical Research Fellow
September 2015 - present
Universitätsklinikum Tübingen
Position
  • Professsor
April 2012 - September 2015
University of Oxford
Position
  • MRC Clinical Research Fellow

Publications

Publications (113)
Article
Full-text available
The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) system represents a powerful gene-editing tool and could enable treatment of blinding diseases of the retina. As a peptide of bacterial origin, we investigated the immunogenic potential of Cas9 in models of retinal immunocompetent cells: human microgli...
Article
Background/aims Voretigene neparvovec (VN) is the first and only subretinal gene therapy approved by the Food and Drug Administration and European Medicines Agency. Real-world application has started in 2018 in patients with vision impairment due to biallelic retinal pigment epithelium ( RPE ) 65 mutation-associated inherited retinal degenerations....
Article
Full-text available
Purpose: Autosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype--phenotype correlation. M...
Article
Gene therapeutic approaches promise treatment or even a cure of diseases that were previously untreatable. Retinal gene therapies tested in clinical trials comprise a wide range of different strategies, including gene supplementation therapies, in vivo gene editing, modulation of splicing mechanisms, or the suppression of gene expression. To guaran...
Article
Full-text available
Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model...
Article
Full-text available
Stargardt’s disease (STGD1) is caused by mutations in the ABCA4 gene. Different lesions characterised by decreased autofluorescence levels are found in fundus autofluorescence (FAF) from STGD1 patients and could be used as outcome indicators for disease progression. We investigated the fate of foci with reduced autofluorescence (FRA) within the het...
Article
Gene therapy is a treatment concept that uses in most cases viral vectors to deliver a therapeutic transgene to target cells. Although the idea of gene therapy dates back over 50 years ago, due to the complexity of the treatment concept, it took until the last decade that the responsible agencies like FDA and EMA recommended the first gene therapy...
Article
b>Hintergrund: Voretigen Neparvovec ist ein gentherapeutischer Wirkstoff zur Behandlung von Netzhautdystrophien, die durch biallelische RPE65 -Mutationen verursacht werden. In der vorliegenden Studie berichten wir über eine neuartige und objektive Beurteilung der retinotopen Wiederherstellung der Photorezeptoren. Methoden: Sieben (7) Augen von 5 Pa...
Article
Purpose Subretinal injections are commonly used in retinal gene therapy procedures to deliver adeno associated virus (AAV) to photoreceptors and RPE cells. Here we present an optimized surgical protocol to minimize off-target application of AAV in the vitreous, which in turn reduces the risk of extensive biodistribution and inflammation, ultimately...
Article
Full-text available
Purpose: The purpose of this study was to evaluate whether clinical grade recombinant adeno-associated virus serotype 8 (rAAV8) leads to increased appearance of hyper-reflective foci (HRF) in the retina of non-human primates (NHPs) following subretinal gene therapy injection. Methods: Different doses of rAAV8 vector (rAAV8. human phosphodiesterase...
Article
Inherited retinal dystrophies (IRD) have been studied since their recognition by Franz Donders and Albrecht von Graefe. It nevertheless took 100 years for a causal therapy to take shape in the form of gene therapy: The approval of Voretigen Neparvovec (VN) for the treatment of hereditary retinal dystrophies due to RPE65 mutations was thus a signifi...
Article
Full-text available
Background Voretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue. Methods Seven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations...
Article
Importance Treatment trials require sound knowledge on the natural course of disease. Objective To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial. Design, Setti...
Article
Full-text available
Importance Achromatopsia linked to variations in the CNGA3 gene is associated with day blindness, poor visual acuity, photophobia, and involuntary eye movements owing to lack of cone photoreceptor function. No treatment is currently available. Objective To assess safety and vision outcomes of supplemental gene therapy with adeno-associated virus (...
Article
Full-text available
Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patien...
Article
Importance Choroideremia (CHM) is a rare, degenerative, genetic retinal disorder resulting from mutation of the CHM gene, leading to an absence of functional ras-associated binding escort protein 1 (REP1). There is currently no approved treatment for CHM. Objective To assess the safety and efficacy of retinal gene therapy with an adeno-associated...
Article
Zusammenfassung Seit ihrer Erstbeschreibung im Jahr 1872 herrscht um den natürlichen Verlauf der Choroideremie eine rege und in Teilen bis heute andauernde akademische Debatte. Aufgrund der Seltenheit der Erkrankung verlief diese traditionell weitgehend am Rande des klinisch geprägten Interessenhorizonts. Nun jedoch hat die Entwicklung grundlegend...
Chapter
Optical coherence tomography (OCT) is an invaluable technique to perform noninvasive retinal imaging in small animal models such as mice. It provides virtual cross sections that correlate well with histomorphometric data with the advantage that multiple iterative measurements can be acquired in timeline analyses to detect dynamic changes and reduce...
Chapter
Ocular anatomy and physiology in cynomolgus monkeys (Macacca fascicularis) are very similar to that found in the human visual system. Therefore and despite significant ethical and economical implications, these animals constitute an excellent model system for toxicology and biodistribution studies in the development of new and meaningful treatment...
Poster
Full-text available
To report longitudinal changes in visual acuity over 20 months of participants with Choroideremia (CHM) in the NIGHT prospective, multi-center, observational study (NCT03359551); the largest natural history study for CHM.
Poster
Full-text available
To report on the emerging efficacy and safety profile of AAV2-REP1 (NSR-REP1), an investiagtional gene therapy for Choroideremia (CHM), using individual patient data (IPD) meta-analysis of 4 clinical trials.
Poster
Full-text available
To report on the immunogenicity and vector shedding potential of NSR-REP1, an investigational gene therapy for the treatment of Choroideremia.
Article
Purpose: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1). Methods: THOR (NCT0267153...
Article
Background/aims The study aims to investigate changes in the optic nerve sheath diameter (ONSD) at high altitude and to assess correlation to optic disc oedema (ODE) and acute mountain sickness (AMS). This investigation is part of the Tübingen High Altitude Ophthalmology study. Methods Fourteen volunteers ascended to 4559 m for 4 days before retur...
Article
Full-text available
Purpose: The purpose of this study was to characterise alterations in colour discrimination in a cohort of patients with choroideremia prior to gene therapy, using a test previously validated for use in patients with retinal dystrophies. Methods: We tested 20 eyes of 10 patients with a diagnosis of choroideremia and an age-matched cohort of 10 e...
Article
Full-text available
Introduction X-linked retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene is the most common form of recessive RP. The phenotype is characterised by its severity and rapid disease progression. Gene therapy using adeno-associated viral vectors is currently the most promising therapeutic approach. However...
Article
Full-text available
Purpose: Mutations in retinitis pigmentosa GTPase regulator (RPGR) cause 70% to 90% of X-linked retinitis pigmentosa (XLRP3) cases, making this gene a high-yield target for gene therapy. This study analyzed the utility of relevant clinical biomarkers to assess symmetry and rate of progression in XLRP3. Methods: A retrospective, cross-sectional a...
Article
Full-text available
Purpose: Despite ever-growing adoption of subretinal (SRi) and intravitreal injections (IVTi) in ocular gene therapy trials, concerns regarding possible deleterious effects of the SRi on the outer retina are yet to be addressed. SRi offers several advantages over IVTi, such as a better photoreceptor transduction efficiency and a limited off-target...
Article
Full-text available
X-linked retinitis pigmentosa (XLRP) is generally a severe form of retinitis pigmentosa, a neurodegenerative, blinding disorder of the retina. 70% of XLRP cases are due to mutations in the retina-specific isoform of the gene encoding retinitis pigmentosa GTPase regulator (RPGRORF15). Despite successful RPGRORF15 gene replacement with adeno-associat...
Article
Aims: The aim of the study was to quantify changes of intraocular pressure (IOP) during exposure to 4559 m using the state-of-the-art method of Goldmann applanation tonometry for IOP measurement and to detect correlations between IOP and acute mountain sickness (AMS) in a prospective manner. Methods: IOP was measured using a Goldmann applanation...
Article
Full-text available
Purpose: To establish a feasible and sensitive pupillographic protocol to assess outer and inner retinal function for the first gene therapy trial in achromatopsia patients (ACHM) with mutations in CNGA3. Methods: Twenty-seven CNGA3-ACHM patients and 22 age-matched control subjects were tested using chromatic pupillography. Three different proto...
Article
In ophthalmology, regenerative medicine is rapidly becoming a reality. Cell based treatment strategies in end stage retinal degeneration may be of therapeutic value, whatever the mechanism of disease mechanism. However, while corneal transplantation is commonly performed with excellent results, many obstacles must be overcome before retinal transpl...
Article
Background Many retinal gene therapy clinical trials require subretinal injections of small volumes of adeno-associated viral (AAV) vector solutions in patients with retinal dystrophies, using equipment not specifically designed for this purpose. We therefore evaluated an optimised injection system in order to identify variables that might influenc...
Article
Mutations in a large number of genes cause retinal degeneration and blindness with no cure currently available. Retinal gene therapy has evolved over the last decades to become a promising new treatment paradigm for these rare disorders. This article reflects on the ideas and concepts arising from basic science towards the translation of retinal ge...
Article
Gene therapy for inherited retinal diseases (IRDs) is currently being validated in several clinical trials and is becoming a promising therapeutic option for these previously incurable diseases. The aim of this review is to give an overview of the concept, the application and the challenges associated with gene therapy. In particular, the pertinenc...
Article
Full-text available
Due to an ageing population the incidence and prevalence of retinal diseases and visual disabilities will continue to grow. A great number of patients would principally be able to benefit from a stem cell-based therapy. To introduce readers to the terminology and current concepts associated with stem cell therapy in ocular research and to provide a...
Article
This study aimed to quantify the impact of high altitude on choroidal thickness and relate changes of altered choroidal blood flow to clinical parameters and acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. Enhanced depth imaging spectral-domain optical coherence tomography was used to qu...
Article
Full-text available
Choroideremia (CHM) is a X-chromosomal disorder leading to blindness by progressive degeneration of choroid, retinal pigment epithelium (RPE), and retinal neurons. A current clinical gene therapy trial (NCT01461213) showed promising safety and efficacy data in a carefully selected patient population. The present study was performed to shed light on...
Article
Full-text available
Purpose: To investigate the biocompatibility of the new cyanine dye: 3,3'-Di-(4-sulfobutyl)-1,1,1',1'-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function. Methods: DSS at a concentration of 0.5% was applied via...
Article
Full-text available
The most common altitude-related symptom, high-altitude headache (HAH), has recently been suggested to originate from restricted cerebral venous drainage in the presence of increased inflow caused by hypoxia. In support of this novel hypothesis, retinal venous distension was shown to correlate with the degree of HAH. We quantified for the first tim...
Article
Full-text available
Aims: High altitude provides environmental conditions with dry air and cold temperatures that may facilitate the development of dry eye symptoms. This study investigated, for the first time, the quality of the tear film during high altitude exposure in healthy subjects. This study is related to the Tübingen High Altitude Ophthalmology (THAO) study...
Article
As impaired S-cone function has been reported psychophysically this study assessed S-cone function during high altitude exposure using electroretinography (ERG) and investigated a possible association with severity of acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. Standard ERG equipment...
Article
Different strategies for the treatment of inherited photoreceptor degeneration are currently being investigated, with each of these approaches facing specific challenges. Gene therapy, for instance, may be feasible only for genetically well-defined pathologies. However, inherited retinal disorders are genetically highly heterogeneous and early onse...
Article
Full-text available
This study aimed to quantify the pupillary light reaction during high altitude exposure using the state of the art Compact Integrated Pupillograph (CIP) and to investigate a potential correlation of altered pupil reaction with severity of acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. P...
Article
Full-text available
Background: The primary objective of this bi-center explorative pilot study was the quantitative assessment of visual field defects and retinal nerve fiber layer thickness (RNFT) over 6 months in patients with acute non-arteritic anterior ischemic optic neuropathy (NAION), in order to elucidate the natural course of NAION and provide a reference d...
Article
The visual field is retinotopically represented in early visual areas. It has been suggested that when adult primary visual cortex (V1) is deprived of normal retinal input it is capable of large-scale reorganisation, with neurons inside the lesion projection zone (LPZ) being visually driven by inputs from intact retinal regions. Early functional ma...
Article
Author Contributions: Dr Gekeler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Willmann, Gekeler. Acquisition of data: Willmann, Fischer, Schatz, Schommer, Gekeler. Analysis and interpretation of data: Willmann, Fischer, Schatz,...
Article
Purpose: This study aimed to quantify the impact of exposure to high altitude on individual layers of the cornea in regard to central corneal thickness (CCT) and the geometry of the anterior chamber angle (ACA). This work is related to the Tübingen High Altitude Ophthalmology study. Methods: Anterior segment spectral domain optical coherence tom...
Article
While hypoxia plays a key role in the pathophysiology of many common and well-studied retinal diseases, little is known about the effects of high altitude hypoxia on retinal function. The aim of the current study was to assess retinal function during exposure to high altitude hypoxia using electroretinography (ERG). This work is related to the Tübi...
Article
Full-text available
To monitor viability of implanted genetically engineered and microencapsulated human stem cells (MicroBeads) in the mouse eye, and to study the impact of the beads and/or xenogenic cells on retinal integrity. MicroBeads were implanted into the subretinal space of SV126 wild type mice using an ab externo approach. Viability of microencapsulated cell...
Data
Processing of MicroBeads in vitro. (A) Bright field (left) and fluorescence (right) microscopy of MicroBeads at day 0 (d0), when MicroBeads from the identical batch were implanted in vivo (Fig. S2). (B) Iterative recording of MicroBeads in vitro at day 10 (d10), when cSLO recording and tissue processing was performed in the animal in parallel (Fig....
Data
Confocal image of cryosection and in vivo cSLO imaging data 10 days post surgery. Top panel shows 10 µm thick cryosection with a MicroBead containing eGFP positive cells in close proximity of the injection site (asterisk). In vivo autofluorescence at the same site of this individual animal (bottom) shows far more eGFP positive cells only minutes be...
Data
Indirect immunofluorescence revealed no induction of VEGF in response to subretinal MicroBead implantation. Indirect immunofluorescence of anti-VEGF of retinal cryosections at the site of MicroBead implantation (A) in 800 µm distance of the implantation -site (B) and of un-implanted control mouse. Indirect immunofluorescence of anti-VEGF of rd1 (D)...
Data
En face and virtual cross sections of MicroBeads 120 days post surgery (PS). Individual location of the optic disc with its main vessels are indicated graphically for better orientation and arrows highlight the eGFP fluorescence signal originating from the implanted MicroBeads. (TIF)
Article
Optical coherence tomography (OCT) is an invaluable technique to perform noninvasive retinal imaging in small animal models such as mice. It provides virtual cross sections that correlate well with histomorphometric data with the advantage that multiple iterative measurements can be acquired in time line analyses to detect dynamic changes and reduc...
Data
Retinal fundus autofluorescence (FAF) recordings of CTRL and BMD monkey. Signal strength differs to some degree between CTRL and BMD animals, while distribution does not demonstrate any significant pathology seen in other forms of macular dystrophies such as a bulls eye pattern of hyper-/hypo-fluorescent rings of FAF signal.
Article
Full-text available
Background Reduction of retinal nerve fibre layer (RNFL) thickness was shown as part of the neurodegenerative process in a range of different neurodegenerative pathologies including Alzheimer ́s disease (AD), idiopathic Parkinson ́s disease (PD), spinocerebellar ataxia (SCA) and multiple system atrophy (MSA). To further clarify the specificity of R...