An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study.

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus 2 (AAV2) vector encoding the cDNA of Rab escort protein 1 (REP1), augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). Up to 0.1 mL of timrepigene emparvovec, containing 1×1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intra-surgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec and 53 completed the study. Visual acuity was generally maintained in both eyes, independent of intra-surgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post-hoc analyses found these were not associated with clinically significant vision loss at Month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of anti-vector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced visual acuity after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

Magnon interactions in a moderately correlated Mott insulator.

Quantum fluctuations in low-dimensional systems and near quantum phase transitions have significant influences on material properties. Yet, it is difficult to experimentally gauge the strength and importance of quantum fluctuations. Here we provide a resonant inelastic x-ray scattering study of magnon excitations in Mott insulating cuprates. From the thin film of SrCuO2, single- and bi-magnon dispersions are derived. Using an effective Heisenberg Hamiltonian generated from the Hubbard model, we show that the single-magnon dispersion is only described satisfactorily when including significant quantum corrections stemming from magnon-magnon interactions. Comparative results on La2CuO4 indicate that quantum fluctuations are much stronger in SrCuO2 suggesting closer proximity to a magnetic quantum critical point. Monte Carlo calculations reveal that other magnetic orders may compete with the antiferromagnetic Néel order as the ground state. Our results indicate that SrCuO2-due to strong quantum fluctuations-is a unique starting point for the exploration of novel magnetic ground states.

Dose-Dependent Progression of Chorioretinal Atrophy at the Injection Site After Subretinal Injection of rAAV2/8 in Nonhuman Primates.

Objective: Progressive retinal atrophy has been described after subretinal gene therapy utilizing the adeno-associated virus (AAV) vector platform. To elucidate whether this atrophy is a consequence of inherent properties of AAV, or if it is related to the surgical trauma of subretinal delivery, we analyzed data from an Investigational New Drug-enabling study for PDE6A gene therapy in nonhuman primates. Design: Animal study (nonhuman primates), retrospective data analysis. Subjects: Forty eyes of 30 healthy nonhuman primates (macaca fascicularis) were included in the analysis. Two AAV dose levels (low: 1x10E11, high: 1x10E12) were compared with sham injection (balanced saline solution; BSS). Twenty untreated eyes were not analyzed. Methods: Animals were treated with a sutureless 23G vitrectomy and single subretinal injections of AAV.PDE6A and/or BSS. The follow-up period was 12 weeks. Atrophy development was followed using fundus autofluorescence (AF), OCT, fluorescence angiography, and indocyanine green angiography. Main Outcome Measures: Area [mm2] of retinal pigment epithelium atrophy on AF. Presence of outer retinal atrophy on optical coherence tomography. Area [mm2] of hyperfluorescence in fluorescence angiography and hypofluorescence in indocyanine green angiography. Results: Progressive atrophy at the injection site developed in 54% of high-dose-treated, 27% of low-dose-treated, and 0% of sham-treated eyes. At the end of observation, the mean ± SD area of atrophy in AF was 1.19 ± 1.75 mm2, 0.25 ± 0.50 mm2, and 0.0 ± 0.0 mm2, respectively (sham × high dose: P = 0.01). Atrophic lesions in AF (P = 0.01) and fluorescence angiography (P = 0.02) were significantly larger in high-dose-treated eyes, compared with sham-treated eyes. Rate of progression in high-dose-treated eyes was 4.1× higher compared with low-dose-treated eyes. Conclusion: Subretinal injection of AAV.PDE6A induced dose-dependent, progressive retinal atrophy at the site of injection. Findings from multimodal imaging were in line with focal, transient inflammation within the retina and choroid and secondary atrophy. Atrophic changes after gene therapy with AAV-based vector systems are not primarily due to surgical trauma and increase with the dose given. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retention Rates of Genetic Therapies Based on AAV Serotypes 2 and 8 Using Different Drug-Delivery Materials.

The purpose of this study was to compare the retention rate of Adeno-associated viral vector (AAV) gene therapy agents within different subretinal injection systems. The retention of AAV serotype 2-based voretigene neparvovec (VN) and a clinical-grade AAV serotype 8 vector within four different subretinal cannulas from two different manufacturers was quantified. A standardized qPCR using the universal inverted terminal repeats as a target sequence was developed. The instruments compared were the PolyTip® cannula 25 g/38 g by MedOne Surgical, Inc., Sarasota, FL, USA, and three different subretinal injection needles by DORC, Zuidland, The Netherlands (1270.EXT Extendible 41G subretinal injection needle (23G), DORC 1270.06 23G Dual bore injection cannula, DORC 27G Subretinal injection cannula). The retention rate of VN and within the DORC products (10-28%) was comparable to the retention rate (32%) found for the PolyTip® cannula that is mentioned in the FDA-approved prescribing information for VN. For the AAV8 vector, the PolyTip® cannula showed a retention rate of 14%, and a similar retention rate of 3-16% was found for the DORC products (test-retest variability: mean 4.5%, range 2.5-20.2%). As all the instruments tested showed comparable retention rates, they seem to be equally compatible with AAV2- and AAV8-based gene therapy agents.

Improvements of complex post-traumatic stress disorder symptoms during a multimodal psychodynamic inpatient rehabilitation treatment - results of an observational single-centre pilot study.

Background: Complex post-traumatic stress disorder (CPTSD) describes chronic disturbances in self-organization (i.e. affect dysregulation; negative self-concept; severe difficulties in relationships) which are frequently observed in survivors of prolonged, repeated or multiple traumatic stressors. So far, evidence of psychodynamic treatment approaches for CPTSD is scarce.Methods: In this single-centre observational pilot study, symptom change during a 6-week psychodynamic inpatient treatment in a multimodal psychosomatic rehabilitation centre was evaluated using repeated measures analyses of variance (ANOVAs). Patients completed questionnaires on PTSD and CPTSD symptoms (ITQ), anxiety, depression and somatization (BSI-18), functional impairment (WHODAS) and epistemic trust, mistrust and credulity (ETMCQ) before (T1) and at the end of treatment (T2). A hierarchical linear regression analysis was calculated to identify factors associated with improved CPTSD symptoms.Results: A total of n = 50 patients with CPTSD were included in the study, of whom n = 40 (80%) completed treatment. Patients reported a significant reduction of CPTSD symptoms during treatment with a large effect size (-3.9 points; p < .001; η2 = .36), as well as a significant reduction of psychological distress (p < .001; η2 = .55) and functional impairment (p < .001; η2 = .59). At the end of treatment, 41.0% of patients no longer fulfilled the diagnostic criteria for CPTSD. Changes in epistemic stance included improved epistemic trust (ß = -.34, p = .026) and decreased epistemic credulity (ß = .37, p = .017), which together with lower age (ß = .43, p = .012) and lower depression levels at baseline (ß = .35, p = .054) were significantly associated with baseline adjusted mean change of CPTSD symptoms during therapy and explained 48% of its variance.Discussion: In our study, patients reported a significant reduction of CPTSD symptoms and comorbid symptoms during a multimodal psychodynamic inpatient rehabilitation treatment. Improved epistemic trust may facilitate the establishment of a trusting therapeutic relationship, thus fostering an environment of openness for knowledge transfer (i.e. social learning) and the exploration of diverse viewpoints and perspectives in the therapeutic process.

Complex post-traumatic stress disorder (CPTSD) is a condition often found in individuals who have experienced severe trauma, such as childhood abuse or torture.A study involving 50 patients with CPTSD showed significant improvements in symptoms and overall quality of life after undergoing a 6-week integrative multimodal psychodynamic inpatient rehabilitation treatment.The study also highlighted that improvement in epistemic trust could be a potential mechanism of change contributing to the positive therapeutic outcomes.

Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

RATIONALE: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. AIMS: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. METHODS: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. STUDY OUTCOMES: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. DISCUSSION: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

An analytical strategy for challenging members of the microplastic family: Particles from anti-corrosion coatings.

Potentially hazardous particles from paints and functional coatings are an overlooked fraction of microplastic (MP) pollution since their accurate identification and quantification in environmental samples remains difficult. We have applied the most relevant techniques from the field of microplastic analysis for their suitability to chemically characterize anti-corrosion coatings containing a variety of polymer binders (LDIR, Raman and FTIR spectroscopy, Py-GC/MS) and inorganic additives (ICP-MS/MS). We present the basis of a possible toolbox to study the release and fate of coating particles in the (marine) environment. Our results indicate that, due to material properties, spectroscopic methods alone appear to be unsuitable for quantification of coating/paint particles and underestimate their environmental abundance. ICP-MS/MS and an optimized Py-GC/MS approach in combination with multivariate statistics enables a straightforward comparison of the multi-elemental and organic additive fingerprints of paint particles. The approach can improve the identification of unknown particles in environmental samples by an assignment to different typically used coating types. In future, this approach may facilitate allocation of emission sources of different environmental paint/coating particles. Indeed, future work will be required to tackle various remaining analytical challenges, such as optimized particle extraction/separation of environmental coating particles.

A Prospective, Observational, Non-interventional Clinical Study of Participants With Choroideremia: The NIGHT Study.

PURPOSE: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression. DESIGN: A prospective, observational, multicenter cohort study. METHODS: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed. RESULTS: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2). No assessment-related serious adverse events occurred. CONCLUSIONS: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.

Real-World Safety and Effectiveness of Voretigene Neparvovec: Results up to 2 Years from the Prospective, Registry-Based PERCEIVE Study.

Voretigene neparvovec (VN) is the first available gene therapy for patients with biallelic RPE65-mediated inherited retinal dystrophy who have sufficient viable retinal cells. PERCEIVE is an ongoing, post-authorization, prospective, multicenter, registry-based observational study and is the largest study assessing the real-world, long-term safety and effectiveness of VN. Here, we present the outcomes of 103 patients treated with VN according to local prescribing information. The mean (SD) age was 19.5 (10.85) years, 52 (50.5%) were female, and the mean (SD) duration of the follow up was 0.8 (0.64) years (maximum: 2.3 years). Thirty-five patients (34%) experienced ocular treatment-emergent adverse events (TEAEs), most frequently related to chorioretinal atrophy (n = 13 [12.6%]). Eighteen patients (17.5%; 24 eyes [13.1%]) experienced ocular TEAEs of special interest, including intraocular inflammation and/or infection related to the procedure (n = 7). The mean (SD) changes from baseline in full-field light-sensitivity threshold testing (white light) at month 1, month 6, year 1, and year 2 were -16.59 (13.48) dB (51 eyes), -18.24 (14.62) dB (42 eyes), -15.84 (14.10) dB (10 eyes), and -13.67 (22.62) dB (13 eyes), respectively. The change in visual acuity from baseline was not clinically significant. Overall, the outcomes of the PERCEIVE study are consistent with the findings of VN pivotal clinical trials.

Outcomes and Adverse Effects of Voretigene Neparvovec Treatment for Biallelic RPE65-Mediated Inherited Retinal Dystrophies in a Cohort of Patients from a Single Center.

Our study evaluated the morphological and functional outcomes, and the side effects, of voretigene neparvovec (VN) gene therapy for RPE65-mediated inherited retinal dystrophies (IRDs) in 12 eyes (six patients) at the Oxford Eye Hospital with a mean follow-up duration of 8.2 (range 1-12) months. All patients reported a subjective vision improvement 1 month after gene therapy. Best-corrected visual acuity (BCVA) remained stable (baseline: 1.28 (±0.71) vs. last follow-up: 1.46 (±0.60); p = 0.25). Average white Full-Field Stimulus Testing (FST) showed a trend towards improvement (baseline: -4.41 (±10.62) dB vs. last follow-up: -11.98 (±13.83) dB; p = 0.18). No changes in central retinal thickness or macular volume were observed. The side effects included mild intraocular inflammation (two eyes) and cataracts (four eyes). Retinal atrophy occurred in 10 eyes (eight mild, two severe) but did not impact FST measurements during the follow-up period. Increased intraocular pressure (IOP) was noted in three patients (six eyes); four eyes (two patients) required glaucoma surgery. The overall safety and effectiveness of VN treatment in our cohort align with previous VN clinical trials, except for the higher occurrence of retinal atrophy and increased IOP in our cohort. This suggests that raised IOP and retinal atrophy may be more common than previously reported.

Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial.

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .

Weight loss induced alleviation of sleep-disordered breathing is associated with improvement of non-alcoholic fatty liver disease.

INTRODUCTION: Sleep-disordered breathing (SDB) and non-alcoholic fatty liver disease (NAFLD) are both common comorbidities in obese patients. Structured weight loss programs are effective and can reduce the incidence and severity of obesity-related comorbidities. The objective of the present analysis is to test whether weight loss induced alleviation of SDB is a predictor for improvement of NAFLD. METHODS: Obese participants underwent a standardized non-surgical 3 months weight reduction program (800 kilocalories per day with low carbohydrate and fat content). Abdominal sonography for NAFLD (grade 0 to 3) and monitoring for SDB (defined as apnea-hypopnea index [AHI] ≥ 15/h) were performed at baseline and after 3 months. Alleviation of SDB was defined as a shift from AHI≥ 15/h to <15/h. RESULTS: 48 patients (48% female, age 42 ± 12 years, body-mass index 40.3 ± 8.1 kg/m2, AHI 14 ± 17/h, 85% NAFLD grade ≥1) participated in the weight loss program. In contrast to the no SDB group, in patients with SDB weight loss of 27.1 ±0 .9 kg (8.4 ± 2.8 kg/m2) after three months was paralleled by a reduction in AHI (-22 ± 17/h), prevalence of SDB (from 31% to 13%), and oxidized low-density lipoprotein (-13 ± 11 U/l). In individuals with preexisting SDB NAFLD grade improved more (2 versus 1, p<0.001) and was at a lower degree at 3 months than in those without SDB (0 versus 1, p = 0.015). In multivariable analysis models, SDB at baseline was associated with improvement of NAFLD grade (B 0.908; 95% CI 0.125, 1.691; p = 0.024), independently of age, sex, and BMI (each p>0.05, respectively). Decreasing BMI (B 0.16 [95%-CI 0.08; 0.23], p<0.001) and alleviation of SDB (B 0.90 [95%-CI 0.21; 1.58], p = 0.012) were independently associated with improvement of NAFLD grade. CONCLUSION: Preexisting SDB and weight loss induced alleviation of SDB are predictors for improvement in NAFLD grade, independent of the extent of weight loss. SDB may contribute to the pathogenesis of NAFLD via SDB-induced oxidative stress and inflammation, but the causal mechanism remains unclear.

Choroideremia: The Endpoint Endgame.

Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.

Future emergence of new ecosystems caused by glacial retreat.

Glacier shrinkage and the development of post-glacial ecosystems related to anthropogenic climate change are some of the fastest ongoing ecosystem shifts, with marked ecological and societal cascading consequences1-6. Yet, no complete spatial analysis exists, to our knowledge, to quantify or anticipate this important changeover7,8. Here we show that by 2100, the decline of all glaciers outside the Antarctic and Greenland ice sheets may produce new terrestrial, marine and freshwater ecosystems over an area ranging from the size of Nepal (149,000 ± 55,000 km2) to that of Finland (339,000 ± 99,000 km2). Our analysis shows that the loss of glacier area will range from 22 ± 8% to 51 ± 15%, depending on the climate scenario. In deglaciated areas, the emerging ecosystems will be characterized by extreme to mild ecological conditions, offering refuge for cold-adapted species or favouring primary productivity and generalist species. Exploring the future of glacierized areas highlights the importance of glaciers and emerging post-glacial ecosystems in the face of climate change, biodiversity loss and freshwater scarcity. We find that less than half of glacial areas are located in protected areas. Echoing the recent United Nations resolution declaring 2025 as the International Year of Glaciers' Preservation9 and the Global Biodiversity Framework10, we emphasize the need to urgently and simultaneously enhance climate-change mitigation and the in situ protection of these ecosystems to secure their existence, functioning and values.

Qualitative exploration of the visual function impairments and impacts on vision-dependent activities of daily living in Retinitis Pigmentosa and Leber Congenital Amaurosis: content validation of the ViSIO-PRO and ViSIO-ObsRO measures.

BACKGROUND: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The associated visual impairments have significant impacts on patients' vision-dependent activities of daily living (ADL), mobility, and distal health-related quality of life (HRQoL). To adequately capture patient and caregiver perspectives in clinical trials, patient and observer-reported outcome instruments must demonstrate sufficient evidence of content validity in the target population. This study aimed to explore the patient experience of RP/LCA and assess the content validity of the Visual Symptom and Impact Outcomes PRO (ViSIO-PRO) and ObsRO (ViSIO-ObsRO) instruments in RP/LCA. METHODS: A total of 66 qualitative, combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted (33 adults, 10 adolescents, 8 children and 15 caregivers of children) in the US, France, Germany, and Canada. Patients had a clinical and genetic diagnosis of RP/LCA from a range of genotypes. CE results were used to further inform the development of a conceptual model and CD interviews assessed the relevance and understanding of the 44-item ViSIO-PRO and 26-item ViSIO-ObsRO instruments. Interviews were conducted across two iterative rounds to allow item modifications. RESULTS: Findings were consistent across RP/LCA genotypes. Night blindness, reduced peripheral vision, vision in very bright lighting and light/dark adaptation were the most frequently reported visual function symptoms impacting vision-dependent ADL and mobility. Impacts on distal HRQoL domains were also reported. The ViSIO-PRO and ObsRO items were well understood by participants and relevant across genotypes. The instructions, 7-day recall period and response scales were well understood and endorsed. Participant and expert clinician feedback supported modifications to item wording, the addition of six new ViSIO-PRO items and one new ViSIO-ObsRO item, and the removal of one ViSIO-PRO item due to lack of relevance. CONCLUSIONS: Findings support the content validity of the ViSIO-PRO and ViSIO-ObsRO instruments for use across RP/LCA genotypes. Ongoing research to evaluate the psychometric validity of the instruments will support future use of the instruments as efficacy endpoints in clinical trials and in general clinical practice to track disease severity and impact of disease on functioning.

Retinal Angiomatous Proliferation in a Patient with Retinitis Pigmentosa.

Retinal angiomatous proliferation (RAP) and other types of choroidal neovascularization (CNV) are very rarely reported in patients with retinitis pigmentosa (RP). We present a case report of a 91-year-old patient with an obvious RP phenotype, who presented with a sudden onset of vision worsening and metamorphopsia in the left eye. Genetic testing on the UK inherited retinal disease panel did not identify a pathogenic variant. Multimodal imaging comprising optical coherence tomography (OCT), OCT angiography, and fluorescein and indocyanine green angiography showed a RAP lesion in the left macula. The patient received three treatments of monthly injections of aflibercept, with excellent morphological and functional outcomes. Taking into account the patient's age at presentation of the RAP lesion, it is not clear whether the RAP was associated or coincidental with RP. This case report highlights the importance of possessing an awareness that RAP lesions can occur in RP. Moreover, due to a good response and potential safety concerns with continuous anti-VEGF injections in RP patients, a pro re nata (PRN) regimen might be the safest option.

How to not induce SNAs: The insufficiency of directional force.

People respond faster to smaller numbers in their left space and to larger numbers in their right space. Here we argue that movements in space contribute to the formation of spatial-numerical associations (SNAs). We studied the impact of continuous isometric forces along the horizontal or vertical cardinal axes on SNAs while participants performed random number production and arithmetic verification tasks. Our results suggest that such isometric directional force do not suffice to induce SNAs.

Programmable RNA editing with endogenous ADAR enzymes - a feasible option for the treatment of inherited retinal disease?

RNA editing holds great promise for the therapeutic correction of pathogenic, single nucleotide variants (SNV) in the human transcriptome since it does not risk creating permanent off-targets edits in the genome and has the potential for innovative delivery options. Adenine deaminases acting on RNA (ADAR) enzymes catalyse the most widespread form of posttranscriptional RNA editing in humans and their ability to hydrolytically deaminate adenosine to inosine in double stranded RNA (dsRNA) has been harnessed to change pathogenic single nucleotide variants (SNVs) in the human genome on a transcriptional level. Until now, the most promising target editing rates have been achieved by exogenous delivery of the catalytically active ADAR deaminase domain (ADARDD) fused to an RNA binding protein. While it has been shown that endogenous ADARs can be recruited to a defined target site with the sole help of an ADAR-recruiting guide RNA, thus freeing up packaging space, decreasing the chance of an immune response against a foreign protein, and decreasing transcriptome-wide off-target effects, this approach has been limited by a low editing efficiency. Through the recent development of novel circular ADAR-recruiting guide RNAs as well as the optimisation of ADAR-recruiting antisense oligonucleotides, RNA editing with endogenous ADAR is now showing promising target editing efficiency in vitro and in vivo. A target editing efficiency comparable to RNA editing with exogenous ADAR was shown both in wild-type and disease mouse models as well as in wild-type non-human primates (NHP) immediately following and up to 6 weeks after application. With these encouraging results, RNA editing with endogenous ADAR has the potential to present an attractive option for the treatment of inherited retinal diseases (IRDs), a field where gene replacement therapy has been established as safe and efficacious, but where an unmet need still exists for genes that exceed the packaging capacity of an adeno associated virus (AAV) or are expressed in more than one retinal isoform. This review aims to give an overview of the recent developments in the field of RNA editing with endogenous ADAR and assess its applicability for the field of treatment of IRD.