A very warm welcome to the September 1st, 2025 edition of EURETINA’s web-based digital periodical, “EURETINA Brief”.  EURETINA are delighted for an up-to-date summary briefs on a range of topics of interest to retinal clinicians, specialists and researchers across Europe. This resource was designed to accommodate the very busy schedules of all our members by providing them with a short overview of some new developments and announcements in our field over recent weeks.

The current issue highlights a number of research activities, clinical / regulatory milestones, and market / business developments in our field, including  a “ concept elicitation study” on qualitative interviews for Retinitis pigmentosa (RP) and Choroideremia (CHM); a systematic review of retinal gene therapy on the impact of route administrations and on serious adverse events (SAEs), and; a new gene therapy candidate – “OPGxBEST1” – reporting a FDA clearance from Opus Genetics for an investigational new drug application (IND) for the treatment of bestrophin-1-related IRD.

As in previous issues we have incorporated a feedback section where you can comment on any of the news items or articles under discussion and we very much welcome all contributions.  Previous articles and issues can be found in the archive section on this website.

As always, your increased interaction within the EURETINA web community serves to expand your professional network and keep you up to date with the latest initiatives, activities and research in your field. Our hope is that such cross-fertilisation in an active web-based platform, including our LinkedIn page, will lead to increased collaborative opportunities and ultimately to improved patient care. All readers are invited to submit comments or responses to any of the stories featured and we look forward to hearing from you over the coming month.

Best wishes,

Dr. Gearóid Tuohy

B.Sc., Ph.D., M.Sc. (Clinical Trial Management)

EURETINA

According to the researchers, “concept elicitation” is the process of identifying the symptoms experienced and the functions affected as the result of a given disease and how this has an impact on patients’ lives. The study was typically done through semi-structured qualitative interviews with patients.  Among the 14 symptoms reported, poor night vision/night blindness, difficulty seeing in bright light, and difficulty seeing in low/dim light were experienced by all participants. Over 50% of participants in either condition reported difficulty adapting from bright to dark and vice versa, poor peripheral vision, poor contrast sensitivity, poor distance vision, and poor visual acuity. Symptoms had a significant impact on activities of daily living. Most commonly impacted were the ability to navigate and the use of digital screens (n = 17/17, 100%) as well as physical functioning and work/school-related activities (n = 16/17, 94.1%). These impacts were often exacerbated by environmental factors, navigation and on emotional well-being.  In particular, health-related Quality of Life (HRQoL) impacts associated with emotional wellbeing (n = 13/17, 76.5%).  The study showed that patients reported sadness/depression due to their eye condition (n = 6/13, 46.2%),  and this concern was followed by annoyance/frustration (n = 4/13, 30.8%), guilt/burden (n = 3/13, 23.1%), anxiety/stress (n = 2/13, 15.4%), fear (n = 2/13, 15.4%), anger (n = 2/13, 15.4%), powerlessness (n = 2/13, 15.4%), and embarrassment/ self-consciousness (n = 2/13, 15.4%). All impacts on emotional well-being were mentioned spontaneously and not specifically probed upon during the interviews.

Figure 1. Conceptual model of RP and CHM symptom and impact concepts

Table 1.  Number of RP and CHM patients reporting symptoms to cause or exacerbate impacts

[The research work is licensed under the terms  of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), cited by Rometsch et al., entitled by: “Patient experience in retinitis pigmentosa and Choroideremia- a concept elicitation study in 17 patients based on qualitative interviews”, Orphanet J Rare Dis . 2025 Aug 11;20(1):418.  doi: 10.1186/s13023-025-03713-4].

The researchers summarised that the most frequently reported impacts concerned activities of daily living (100%), emotions (90%), reading (81%), driving (71%), chores and cleaning (62%), navigation (52%), sports/ physical activity (52%), and walking into objects (48%). Impacts were reported to be exacerbated by lighting conditions, unfamiliar environments and weather conditions.  The patient interviews provided insight into the patient experience of RP and CHM to develop a combined conceptual model of the RP and CHM disease experience.  Finally, the researchers commented that, “our findings are suitable to inform recommendations for the development of patient-reported outcome (PRO) and performance outcome (PerfO) measures needed to evaluate novel therapies for both RP and CHM.”

The researchers evaluated SAEs from trial results from inherited retinal disease (IRDs), with the prevalence of all IRDs being 1:1380, and with the most common being retinitis pigmentosa (RP, 1:4,000), Stargardt disease (1:10,000), and choroideremia (CHM, 1:50,000). The most commonly utilised viral vector in retinal diseases is adeno-associated virus type 2 (AAV2) across different serotypes, such as AAV2/2 (RPE tropism) and AAV2/8 (cone photoreceptor tropism) and the three main methods of delivery are intravitreal, subretinal, or suprachoroidal injections. Following a systematic review process, the researchers collected 31 clinical trial studies and SAEs were recorded in 51 out of 438 eyes (11.6%) that received subretinal injections and in 11 out of 348 eyes (3.2%) that received intravitreal injections. There were fewer intravitreal-related SAEs and less vision loss compared to subretinal gene therapy.

Figure 1. Serious adverse event breakdown by injection route. For subretinal trials (A) and intravitreal trials (B), the outer wheels show the proportion of SAE type, while the inner wheel shows the proportion of eyes that experienced vision loss due to the associated SAE. For all injected eyes, the number and percentage of eyes that experienced each SAE are included in the provided table (left columns). For any given SAE, the number and percentage of eyes experiencing vision loss are included in the provided tables (right columns).

[The research work is licensed under the terms  of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), cited by Berger et al., entitled by: “Retinal Viral Gene Therapy: Impact of Route of Administration on Serious Adverse Events—A Systematic Review”, Clinical & Experimental Ophthalmology, 2025; 0:1–19 https://doi.org/10.1111/ceo.14593].

Inflammation was the predominant SAE following intravitreal injections, whereas unexplained vision loss was the most common for subretinal injections. Clinical trials utilising subretinal injections met primary or secondary efficacy endpoints more than intravitreal trials. Eighteen studies (429 eyes) of post-approval LUXTURNA (voretigene neparvovec) were reviewed, and SAEs were reported in 24.7% of eyes, retinal degeneration being most common (20.7%). For 58 animal studies, SAEs were recorded in 17.3% of eyes that received subretinal injections and 8.7% of eyes that received intravitreal injections.  In addition, the researchers commented that the purity and quality of drug production is crucial, in particular to the number of capsids loaded with viral genomes. Some capsids may be empty and some may be full.  Without data being made available on the production process, it will be unclear on what the level of dosage of the gene therapy treatment.  In conclusion, the researchers stated that, “we recommend that future viral gene therapy studies evaluate chorioretinal atrophy (CRA) specifically as an adverse event. Studies should follow their subjects for an extended period, preferably at least a year, to assess the development of CRA. For consistency, viral genomes and capsid particles should both be reported. Additionally, when reporting inflammation, quantitative methods should be used such as Standardisation of Uveitis Nomenclature (SUN). For animal studies, visual function assessments should be included in safety assessments. It is also recommended to use animal disease models, when possible, to accurately assess safety.”

The textbook has now provided a 13^th edition with a clear and straightforward approach to understand without any previous medical or scientific background.  Real-life applications of terminology are provided and each chapter breaks down terms phonetically to support students to master proper pronunciations. Medical report exercises in each chapter utilize chart notes, histories, and reports to give students exercises to practice working with realistic documents. In addition, the textbook provides a companion CD to identify terms by their pronunciation and how to review terms through games, study tips, photographs, video clips, and animations.  An Elsevier website (“Evolve”, https://evolve.elsevier.com) enables how to assess and understand with quizzes for each chapter to identify specific areas for review.

The textbook is well structured throughout, covering from basic word structures and language and running through each body system – digestion, reproduction, cardiovascular, respiratory, musculoskeletal, vision and further on oncology, radiology, nuclear medicine, pharmacology and psychiatry.  There is an additional four comprehensive appendices on plurals, abbreviations, acronyms, and eponyms; normal hematologic reference values and implications of abnormal results and, finally, a compendium of drugs. Finally, there is a “mini-dictionary” and a glossary, included in the textbook, with the definitions and phonetic pronunciation

English, Book ISBN: 9780443107795; page xxi to 1,072 pages (incl. 521 illustrations). Copyright year: 2025; Book format: 216w (mm) x 276h (mm); Publication Date 08-02-2024

The 10^th edition of Kanski’s Clinical Ophthalmology is a comprehensive medical text on general ophthalmology and optometric practice.  The author’s objective was to cover the entire field of ophthalmology “without depending on sub-specialists”, instead, presenting a core of clinical knowledge repository in “a systematic and succinct form”.  This is achieved with 22 comprehensive chapters spanning almost 1,000 pages of in-depth information, including over 2,800 illustrations and images.  The book is a well-presented and laid out content of subject matter, acting as rigorous refence text. There is no bibliography available in the book.

The author is John F. Salmon, MD, FRCS, FRCOphth, Consultant Ophthalmic Surgeon, Oxford Eye Hospital, Oxford, UK and a Specialist Ophthalmologist at Groote Schuur Hospital for nine years. During this period, he received a doctorate on the subject of primary angle-closure glaucoma. He was then appointed to the position of Consultant Ophthalmologist to the Oxford Eye Hospital where he directed glaucoma services for 25 years. He is actively involved in teaching and in 2013 received an “Excellent Teacher” award from the University of Oxford. He has trained 25 Fellows in glaucoma, and has authored more than 100 peer-reviewed papers and seven book chapters.

Elsevier’s new edition have stated that, “Dr. Kanski’s highly effective format of succinct text and visually dynamic presentation” provides students, trainees and experienced practitioners. “Extremely well organized and comprehensive in scope, it provides authoritative, focused guidance on diagnosis and management, facilitating quick comprehension to enhance learning, aid exam preparation, and guide clinical practice.”

Key Features in the new 10^th edition show:

• targeted text, bulleted lists, tables and visual aids to highlight salient points across all ophthalmology subspecialties.
• features more than 2,800 high-quality illustrations, including over 2,000 images depicting both common and rare conditions, with arrows to show the exact pathology.
• includes the latest developments in cataract and refractive surgery, glaucoma, diabetes, macular degeneration, retinal vascular disease, pachychoroid disease, posterior uveitis, inflammatory eye disease, multiple sclerosis, thyroid eye disease, tumors, immunotherapy and genetics.
• contains new, detailed illustrations of eye anatomy; improved case examples; and expanded sections on headache, seventh nerve palsy, cerebral visual impairment and Parkinson disease.
• uses state-of-the-art imaging modalities such as OCT, OCT-A, fundus autofluorescence and ICG angiography to demonstrate subtle choroidal and retinal pathology.
• offers detailed coverage of rare conditions: monkey pox infection, COVID conjunctivitis, silent sinus syndrome, torpedo maculopathy, CRB-1 associated retinal dystrophy, sagging eye syndrome and SLE scleritis.
• an eBook version is included with purchase allowing the reader to access all of the text, figures, and references, with the ability to search, customize your content, make notes and highlights, and have content read aloud.

English, Hardback ISBN: 9780443110993; page (xii) to 968 pages. Copyright year: 2025; Book format: 216w (mm) x 276h (mm); Publication Date 22 Jul 2024

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The book, edited by Christine Dickinson, Ana Hernandez Trillo and Michael Crossland, based at the University of Manchester and Moorfields Eye Hospital NHS Foundation Trust, covers 5 sections comprising a total of 23 chapters and 4 appendices.  The sections include the description and analysis on a definition of low vision, magnification for improving visual performance, visual rehabilitation, clinical procedures and several resources for patients, patient organisations, clinical history record keeping, literature, magnification tools, social services and more.  The text comprise theory, practice and case studies and the final section on Clinical Procedures ranges from everything on scheduling the appointment, the visual assessment, follow-up, prescribing, magnifier selection, spectacle correction, trial in the “real-world”, evaluation and audit, defining success and a selection of case studies and additional commentaries.  The comprehensive resource provides a practical and clear approach with  practising eye care “professionals and students fully up to date with current optical and electronic devices and how they are used in everyday practice”.

Finally, the publisher (Elsevier) are commended to include a “read aloud” initiative in the electronic copy of the book for those who may wish to listen parts of the material and/or follow the reading and listening, combined.  While some of the diction may be difficult to hear the sounds and intonation of the speech with different audiences, it is nonetheless a significant addition to the offering that will likely iterate the e-resources in due course.

English, Paperback ISBN: 9780323876346; eBook ISBN: 9780323876353; page (iii) to 331 pages. Copyright year: 2024; Book format: 216w (mm) x 276h (mm); ISBN# 9780323876346.

Author Information: By Christine Dickinson, BSc PhD FCOptom PGCertHE, Professor of Clinical Optometry and Lead for Undergraduate Masters, Division of Pharmacy and Optometry, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK; Ana Hernandez Trillo, BSc MSc PhD PGDipMEd SFHEA, Senior Lecturer in Optometry, Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK and Michael Crossland, Senior Research Fellow, UCL Institute of Ophthalmology, University College of London and Specialist Optometrist, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

(1) Low Vision Services Consensus Group. Low Vision Services: Recommendations for future service delivery in the UK. London: The Royal National Institute for the Blind, 1999.

(2) Assessment of low vision in developing countries, WHO/PBL/95.48.

(3) Low vision, Chapter 21 (Vision in context), Oxford Handbook of Ophthalmology, 2^nd edition, Alastair K.O. Dennison & Philip I. Murray

Gearóid Tuohy B.Sc., Ph.D. (Genetics), M.Sc. (Clinical Trials & Statistics).
Director, Clinical Trials Research

]]> https://brief.euretina.org/research/x-linked-retinitis-pigmentosa-xlrp-due-to-rpgr-variants-report-new-data-on-actin-dynamics Mon, 10 Jun 2024 07:23:46 +0000 https://brief.euretina.org/?p=3268 Read More »X-linked retinitis pigmentosa (XLRP) due to RPGR variants report new data on actin dynamics. ]]> Researchers based at the MRC Human Genetics Unit, at the University of Edinburgh, and the Western General Hospital (Edinburgh), have reported a new study indicating that disc formation, at the outer segments of the photoreceptors, appears to be an actin-driven process, rather than a passive process or blebbing.    Disc shedding on the outers segments may arise from alterations of the RPGR protein, and localisation of cofilin, an actin-binding protein acting in a central role in cell motility, contraction and transcription regulation.   Research results suggest that RPGR proteins may compromise cofilin activity, and the perturbation of disc shedding results in outer segment abnormalities, retinal stress, photoreceptor degeneration and loss of vision. While the research is at an early stage, the outcomes are significant in their report and modulation of these actin manipulations, in due course, could be targeted therapeutically.

Variants of the retinitis pigmentosa GTPase regulator (RPGR) may lead to X-linked retinitis pigmentosa (XLRP) and the majority of mutations in the gene are found in exon open reading frame 15 (ORF15). It gene encodes a ciliary protein that regulates trafficking of proteins to the outer segment of photoreceptors.  RP affects an estimate of 1 in 3,000 people world-wide, arising from 289 genes to date, while alterations of the RPGR protein may account for 70–90% of X-linked RP (XLRP) and 10-15% of all RP resulting in a severe form of the disease.  The current research report, published in Nature Communications (2024 May 21;15(1):4316), used cryo-electron tomography (cryoET) and immunohistochemistry showing that cofilin localisation to photoreceptor connecting cilium (CC) were in normal retinas, and partially lost in mutated models not seen in cofilin in knockout mice. Co-immunoprecipitation experiments using retinal lysates confirmed endogenous cofilin and the retinal specific isoform of RPGR occur in complex in the retina.

Figure. 1 Photoreceptor disc formation is an actin-driven process. (a) Schematic of a rod photoreceptor depicts the cell’s inner segment (IS) with the highly modified connecting cilium (CC) extending from its apex, containing a microtubule-based axoneme (Ax). From here an expanse of folded membrane extends, forming the outer segment (OS) discs. Basal discs (BD) are continually added at its base. (b) A projection from a tomogram of the basal disc of a wild-type photoreceptor. (c) A slice through a tomographic reconstruction, segmented to highlight the ciliary and disc membranes (green), microtubule-based axoneme (cyan) and microfilaments (purple). Microfilaments extend from the connecting cilium into the basal disc. [Open Access article, under a Creative Commons Attribution 4.0 International License (visit http://creativecommons.org/licenses/by/4.0/) , Megaw et al, Nat Commun. 2024 May 21;15(1):4316.  doi: 10.1038/s41467-024-48639-w].

The Scottish team outlined that cofilin is known to regulate primary cilia length through actin rearrangement and the observation that “cofilin is present in aborted photoreceptor ectosomes when normal disc formation is disrupted further supports this model”. In addition, in their report, the authors stated that, “[n]o treatment currently exists for any form of RP. Whilst gene therapy offers hope, long-term data for the only FDA- and EMA approved gene therapy drug for genetic eye disease is less encouraging. Complementary approaches must therefore be sought. Here, we show that pharmaco-manipulation of actin activity could reverse the underlying cellular phenotypes disrupting disc biogenesis. Further work is required to address the translational potential of our study, specifically to establish if long-term cofilin modulation could slow the retinal degeneration seen in RPGR/XLRP patients”.

This 9^th new edition of the book is now expected to support a wider audience of students and practitioners alike, having done so admirably for almost 60 years. The book provides an excellent balance of theory and practice, allowing both the novice or the more experienced student, to learn and understand the concepts, acquire new knowledge, gain insight into the mechanics of molecular biology and the practical applications of genetics on human disease.  The practical applications, as outlined through “Clinical Cases” in this book, 49 in total, accommodates almost head to toe, from vision (Age-Related Macular Degeneration) to muscle wasting (Charcot-Marie-Tooth Disease) and beyond.

The text covers 20 chapters, including a new chapter from a previous edition on Principles of Clinical Epigenetics, from an earlier edition.  The chapters range from an Introduction to the Human Genome, chapters on structure and function, diversity and variation, Principles of Clinical Cytogenetics and Genome Analysis, Complex Inheritance of Common Multifactorial Disorders, chapters on population genetics, and the genetic basis for disease and inborn errors of metabolism, The Treatment of Genetic Disease and Genetic Counselling and Risk Assessment, and a chapter on Application of Genomics to Medicine and Individualized Health, and finally, Ethical and Social Issues in Genetics and Genomics.  Throughout the text, this edition provides beautiful illustrations for the explanatory content, including an excellent contribution of photographs and images from the Positive Exposureorganization (https://positiveexposure.org), a not-for-profit initiative collating a large portfolio of content from patient and family volunteers.  The book includes almost 600 pages, comprising 543 illustrations in full colour, and a section on Problems proposed at the end of each chapter with Answers to Problems at the end of the book. In addition, this 9^th edition includes  a digital e-book copy, easily accessed through http://ebooks.health.elsevier.com, with a code in the inside cover, and with additional features at the end of the back cover of the book

The new editors of the book, Ronald Cohn, Stephen Scherer and Ada Hamosh, has also summarised new content from previous editions, including:

(1)        moving from the study of genes to genomes in biology and testing;

(2)        increasing awareness of copy number and structural genomic variation in both the population and medical genomic context;

(3)        novel discoveries and application of the functional roles of non-coding RNAs, chromatin-regulation and epigenetics, and how their dysregulation can affect gene expression in disease;

(4)        genetic variation in world-wide populations;

(5)        latest technologies (e.g., genome sequencing) and statistical/informatics approaches, such as polygenic risk scores, used to resolve and interpret them, and;

(6)        the many new genetic diagnoses arising from application of these new principles and technologies (for example, genomic syndromes and ciliopathies).

Each chapter is overseen by a significant cadre of contributing authors working at the frontier of their field.  As a result, readers may expect to continue their education with Genetics and Genomics in Medicine as a “go to” reference for this foundational text for any new students, academics or professionals.

Copyright year: 2024; Book format: 216 width (mm) x 276 height (mm); ISBN# 9780323547628; Contributors #31.

Gearóid Tuohy B.Sc., Ph.D. (Genetics), M.Sc. (Clinical Trials & Statistics).
Director, Clinical Trials Research