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.”

A very warm welcome to the August 15^th, 2025 edition of EURETINA’s web-based digital periodical, “EURETINA Brief”.  EURETINA are delighted to continue our delivery of up-to-date summary briefs on a range of topics of interest to retinal clinicians, specialists and researchers across Europe. This resource is 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 new treatment outcome and natural history registry for inherited retinal disease (IRD) – presented as “THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT”; a review of fundus autofluorescence (FAF) underscoring an indispensable technology for the diagnosis, monitoring and outcome measures of numerous retinal diseases, and; an announcement of 60-week results from 4D-150 “SPECTRA” treatment for DME Phase 3 data reports sustained visual acuity gains.

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

The Fight Inherited Retinal Blindness! (FIRB!) Registry is an expanded registry building on previous modules supported by the Save Sight Registries, a non-profit organisation, also supported with the University of Sydney, Australia.   A committee of six members was overseen the construction of the Fight Inherited Retinal Blindness! Module with a further 11 experts all of whom have a clinical and/or research interest in IRDs.  The web-based Fight Inherited Retinal Blindness! registry records baseline demographic, clinical, and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the Fight Inherited Retinal Blindness! architecture to standardize nomenclature (Mondo: unifying diseases for the world, by the world. medRxiv 2022: 1–12). The registry has developed software that can assign individual diagnoses to one of seven broad phenotypic groups, with minimum datasets dependent on the broad phenotypic group. New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes.

Figure 1. Screengrab of a data entry/presentation page for a patient with IRD secondary to biallelic RPE65 mutations after retinal gene therapy with voretigene neparvovec. Pertinent clinical data (e.g., best-corrected visual acuity, FST results) can be plotted against time as a means of easily tracking disease progression and treatment effects. [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 Simunovic et al., entitled by: “THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT A New Treatment Outcome and Natural History Registry for Inherited Retinal Disease”, Retina, 2025; 45:286–295 ].

According to the researchers, The Fight Inherited Retinal Blindness Registry! was conceived for two purposes: “first, to track the natural history of IRDs, and second, to monitor real-world outcomes in patients receiving emerging treatments, such as gene therapy”. The FIRB! registry provides a rapid means of recording outcomes from treatments, for example, following Luxturna gene therapy (voretigene neparvovec). The outcome measures are those “recommended by both regulatory authorities and professional bodies internationally, making the registry a convenient and rapid means of recording outcomes to assess real world outcomes and for drug monitoring by national authorities”. In addition, FIRB! provides a means of “tracking adverse or unanticipated events—such as the development of chorioretinal atrophy—which has only been reported post regulatory approval in a significant minority of patients undergoing voretigene neparvovec gene therapy”.

Fundus autofluorescence is a non-invasive imaging modality that can map naturally and pathologically occurring fluorophores in the posterior pole, first utilized for in vivo fundus imaging in 1995 characterizing the intrinsic autofluorescent properties of the retina. Technical improvements have developed in the interim utilizing the fluorescent properties of lipofuscin within the retinal pigment epithelium (RPE) to create an image. Lipofuscin, a byproduct of lysosomal breakdown of photoreceptor outer segments, is composed of numerous bisretinoids including A2E, A2PE, isoA2E, and A2-DHP-PE. When subjected to a light source, these bisretinoids absorb blue light with a peak excitation wavelength of 470nm and emit yellow-green light with a peak wavelength of 600nm, depending on the chemical makeup of the lipofuscin. Since many retinal pathologies often lead to RPE dysfunction and an accumulation of lipofuscin, abnormal patterns of autofluorescence (AF) on FAF imaging can act as markers for retinal disease.

Figure 1. Retinoid visual cycle and the origin of fundus autofluorescence signal. An illustration of the retinoid visual cycle that takes place between the retinal pigment epithelium and the outer segments of photoreceptors is shown. Interruption of the visual cycle at any point can lead to the development of inherited retinal degenerations. Accumulation of bisretinoids in retinal pigment epithelium cells as a byproduct of the cycle is the source of fundus autofluorescence signal. [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 Oh et al., entitled by: “Fundus Autofluorescence in Inherited Retinal Disease: A Review”, Cells 2025, 14, 1092].

The researchers explained that FAF is “an indispensable tool in the diagnosis and monitoring of numerous retinal diseases. Across the spectrum of IRDs, including Stargardt disease and pattern dystrophies, RP, choroideremia, and mitochondrial retinopathies, FAF has demonstrated consistent utility in disease diagnosis, monitoring of progression, and guiding prognostication. Several biomarkers for potential clinical trials, such as changes in hyperautofluorescent ring size or area of hypoautofluorescent atrophy, are increasingly being considered as potential outcome measurements in clinical trials. As our understanding of IRDs deepens, FAF will likely remain a mainstay of both clinical care and research.”

Figure 2. Hyperautofluorescent rings in retinitis pigmentosa seen on fundus autofluorescence compared to color fundus photography. (A) Montage color fundus photographs of a 36-year-old patient with autosomal dominant retinitis pigmentosa due to mutations in RHO demonstrate waxy pallor of the optic nerve, vascular attenuation and nasal and inferior bone spicules. (B) 55◦ field fundus autofluorescence demonstrates a central hyperautofluorescent ring, smaller in the right eye than the left, which is not seen on color fundus photographs (green arrows). Areas of both definitely decreased autofluorescence (red arrows) and questionably decreased autofluorescence can be seen (pink arrows). [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 Oh et al., entitled by: “Fundus Autofluorescence in Inherited Retinal Disease: A Review”, Cells 2025, 14, 1092].

In addition, fundus autofluorescence provides a quantitative outcome measure for natural history studies, valuable for subsequently supporting clinical trials from new experimental treatments. The recent US researchers have commented that “such studies have become increasingly common, particularly for genetically defined forms of RP, with many incorporating FAF to monitor disease progression. In the past two years alone, multiple natural history studies for various forms of RP have been described”.  According to the researchers, FAF enables objective quantitative assessment of retinal atrophy to evaluate whether treatment slows disease progression compared to untreated eyes”.

4D-150 is an investigational agent designed to provide sustained delivery of anti-VEGF (aflibercept and anti-VEGF-C) utilizing thecompany’s customized intravitreal vector, R100. 4D-150 is being developed for wet AMD and DME for the purpose of avoidpatients from burdensome injections while preserving vision.  The company’s product candidates are in clinical or preclinical development, not yet been approved for marketing by regulatory authorities.     The company is aimed to align a single Phase 3 clinical trial for both the FDA and EMA, based on data generated for 4D-150 from  two planned Phase 3 clinical trials in ta “4FRONT” wet age-related macular degeneration (wet AMD) program, potentially acceptable as the basis for a marketing authorization application (MAA) submission for 4D-150 in DME.

In the SPECTRA (DME) study, the company reported efficacy results through 60 Weeks from a Phase 3 dose showing a sustained gain of best corrected visual acuity (BCVA) of +9.7 letters and a sustained improvement in anatomic control, with reduction of CST, as measured by optical coherence tomography (OCT), of -174 µm.  Following the announcement, David Kirn, M.D., Co-founder and Chief Executive Officer of 4DMT stated that, “the consistency of dose response, safety and efficacy data we’ve seen with 4D-150 across all patients evaluated in both DME and wet AMD reinforces our belief that 4D-150 has the potential to become a true backbone therapy, and may significantly improve the lives of millions of patients living with retinal vascular disease.  With alignment from both FDA and EMA for a single Phase 3 DME trial to complement the 4FRONT wet AMD program, we believe we have a clear streamlined path to bring 4D-150 to patients with high unmet need”.

A very warm welcome to the August 4^th, 2025 edition of EURETINA’s web-based digital periodical, “EURETINA Brief”.  EURETINA are delighted to continue our delivery of up-to-date summary briefs on a range of topics of interest to retinal clinicians, specialists and researchers across Europe. This resource is 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 small study of severe variants of ABCA4 reports a new genotype–phenotype correlation with Early-Onset Severe Retinal Dystrophy (EOSRD); a clinical study of >3,500 IRD patients reports novel genotype-phenotype associations using optical coherence tomography (OCT) imaging, and; Beacon Therapeutics announce the completion of enrolment for the Phase 2/3 trial for “laru-zova”, for the treatment of XLRP.

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

Figure 1. The spectrum of ABCA4 retinopathy. Representative FAF images are shown for each stage. Individuals with a normal fundus can carry any of these alleles: WT/WT, WT/severe, WT/mild, severe/mildIP, mild/mild, mild/mildIP, or mildIP/mildIP. MildIP, mild with incomplete penetrance; WT, wild type. Images were obtained and modified from Cremers FP et al, Prog Retin Eye Res. 2020;79:100861, (CC-BY license).  [This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, cited by Panneman DM,  et al. Expansion of the ABCA4-associated retinopathy spectrum: Severe variants can be associated with early-onset severe retinal dystrophy. Invest Ophthalmol Vis Sci. 2025;66(6):19. https://doi.org/10.1167/iovs.66.6.19).

As a juvenile form of RP, LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG. LCA was originally identified by a German clinical ophthalmologist, Theodor von Leber in 1869 and the disorder was primarily based on the early infant-onset form of non-syndromic inherited visual loss.  However, following the original description of the infantile disorder, a subsequent milder form of the same disease presented in the 6th and 7th years of life and led to blindness by the age of 30 years, considered to be on the same spectrum as LCA.  This later-onset disease has been referenced by several different names including juvenile and early-onset retinitis pigmentosa, childhood-onset severe retinal dystrophy, Early Onset Severe Retinal Dystrophy (EOSRD) and Severe Early Childhood Onset Retinal Dystrophy (SECORD). A more recent structure for nomenclature, aiming to define the basis as being on genotype rather than phenotype (e.g., RPE65-related LCA), is preferable.  Currently, the researchers studying in Nijmegen, investigated the genetic cause of disease and clinical characteristics in three probands with EOSRD.

The three patients were seen in various ocular genetics and retinal dystrophy clinics from Chicago, IL, USA, Vancouver, Quebec, Canada, and Auckland, New Zealand.

Table 1. Genetic Findings in ABCA4 for Probands 1, 2, and 3. Severity scores are according to Cornelis et al., Am J Hum Genet. 2022;109:498–507 The protein notation of the c.6729+5_6729+19del variant is based on the midigene assay results from Sangermano et al., Genome Res. 2018;28:100–110. [Open Access, Panneman DM,  et al. Expansion of the ABCA4-associated retinopathy spectrum: Severe variants can be associated with early-onset severe retinal dystrophy. Invest Ophthalmol Vis Sci. 2025;66(6):19. https://doi.org/10.1167/iovs.66.6.19)].

Following their analysis, the researchers described “a new genotype–phenotype correlation identified in three EOSRD probands that carry at least two severe variants in ABCA4”. The data showed that two probands carry the same pathogenic, homozygous splice site variant. In addition, extensive studies of the ABCA4 gene in associated conditions such as Stargardt disease (STGD1) and STGD-like macular diseases have revealed late-onset phenotypes, and they commented that “no link with severe early-onset IRDs such as EOSRD or LCA has been found previously”. Using  whole genome sequencing (WGS), the researchers identified two NBAS (neuroblastoma-amplified sequence) variants and a homozygous CNGB3 (cyclic nucleotide gated channel subunit beta 3) variant in probands 1 and 3, respectively.  In summary, the team’s results “expand the phenotypic spectrum of disorders associated with variants in ABCA4”, spanning ages from birth to old age.