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    Research Update 557


    Survey of perspectives of people with inherited retinal diseases on ocular gene therapy in Australia.

    Gene Therapy. 2022 Oct 2

    Mack HG, Britten-Jones AC, McGuinness MB, Chen FK, Grigg JR, Jamieson RV, Edwards TL, De Roach J, O’Hare F, Martin KR, Ayton LN.

    Many gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p < 0.001) and outcomes (p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.

    DOI: 10.1038/s41434-022-00364-z


    Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy.

    Scientific Reports. 2022 Oct 25

    Pfau M, Schmitz-Valckenberg S, Ribeiro R, Safaei R, McKeown A, Fleckenstein M, Holz FG.

    Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332). Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12. Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] + 0.29 z-score units [0.16, 0.42], P < 0.001). The same was evident for eyes treated with pegcetacoplan every other month (+ 0.26 z-score units [0.13, 0.4], P < 0.001). Additionally, eyes treated with pegcetacoplan exhibited a thicker photoreceptor inner segment layer along the 5.16°-contour-line at month 12. These findings suggest that pegcetacoplan could slow GA progression and lead to reduced thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration.

    DOI: 10.1038/s41598-022-22404-9


    Identifying Novel Genes and Variants in Immune and Coagulation Pathways Associated with Macular Degeneration.

    Ophthalmology Science. 2022 Aug 8

    Huan T, Cheng SY, Tian B, Punzo C, Lin H, Daly M, Seddon JM.

    Purpose: To select individuals and families with a low genetic burden for age-related macular degeneration (AMD), to inform the clinical diagnosis of macular disorders, and to find novel genetic variants associated with maculopathies.

    Design: Genetic association study based on targeted and whole-exome sequencing.

    Participants: A total of 758 subjects (481 individuals with maculopathy and 277 controls), including 316 individuals in 72 families. METHODS: We focused on 150 genes involved in the complement, coagulation, and inflammatory pathways. Single-variant tests were performed on 7755 variants shared among ≥ 5 subjects using logistic regression. Gene-based tests were used to evaluate aggregate effects from rare and low-frequency variants (at minor allele frequency [MAF] ≤ 5% or ≤ 1%) in a gene using burden tests. For families whose affected members had a low burden of genetic risk based on known common and rare variants related to AMD, we searched for rare variants (MAF < 0.001) whose risk alleles occurred in ≥ 80% of affected individuals but not in controls. Immunohistochemistry was performed to determine the protein expression of a novel gene (coagulation factor II thrombin receptor-like 2 [F2RL2]) in retinal tissues.

    Main outcome measures: Genotypes and phenotypes of macular degeneration.

    Results: We confirmed the association of a synonymous variant in complement factor H (Ala473, rs2274700, proxy to intronic rs1410996, r 2  = 1) with maculopathy (odds ratio, 0.64; P = 4.5 × 10-4). Higher AMD polygenic risk scores (PRSs) were associated with intermediate and advanced AMD. Among families with low PRSs and no known rare variants for maculopathy, we identified 2 novel, highly penetrant missense rare variants in ADAM15, A disintegrin and metalloprotease, metallopeptidase domain 15 (p.Arg288Cys) and F2RL2 (p.Leu289Arg). Immunohistochemistry analyses revealed F2RL2 protein expression in cone photoreceptor outer segments and Müller glia cells of human and pig retinas. Coagulation factor II thrombin receptor-like 2 expression appeared increased in fibrotic areas in advanced AMD samples with neovascularization, suggesting that F2RL2 may play a role in the progression to advanced macular disease.

    Conclusions: New missense rare variants in the genes ADAM15 and F2RL2 were associated with maculopathies. Results suggest that novel genes related to the coagulation and immune pathways may be involved in the pathogenesis of macular diseases.

    DOI: 10.1016/j.xops.2022.100206


    Longitudinal analysis of aqueous humour cytokine expression and OCT-based imaging biomarkers in retinal vein occlusions treated with anti-vascular endothelial growth factor therapy in the IMAGINE study.

    Eye (London, England). 2022 Oct 11.

    Arepalli S, Wykoff CC, Abraham JR, Lunasco L, Yu H, Hu M, Srivastava SK, Reese JL, Brown D, Ehlers JP.

    Background/objectives: Retinal vein occlusion (RVO) is the second most common retinal vascular disorder. Despite promising advances with anti-VEGF therapy, select patients are unresponsive to therapy. A precision medicine-based approach for therapeutic decision-making based on underlying biomarkers may facilitate treatment based on the underlying pathway. This study aims to identify the baseline and longitudinal cytokine profiles of RVO-related macular oedema and correlating these expression profiles with higher order OCT features using a novel retinal segmentation and feature extraction platform.

    Subjects/methods: The IMAGINE study is a post-hoc assessment of aqueous humour cytokines with correlation to higher level analysis of imaging studies. OCT scans underwent machine learning enhanced segmentation of the internal limiting membrane (ILM), ellipsoid zone (EZ) and retinal pigment epithelium (RPE), as well as evaluating volumetric fluid metrics. Samples of aqueous humour were obtained at baseline, as well as months 4 and 9 prior to treatment. These samples were analysed for the expression of multiple cytokines. Patients were divided into Responders and Non-Responders based on OCT profiles. Additionally, patients were categorised as a Rebounder if their CST increased by 50% after initial improvement.

    Results: Twenty-six eyes were included. The OCT-based response schema identified 21 Responders (81%) and 5 Non-Responders (19%). VEGF levels directly correlated with intraretinal fluid volume and angiogenin was inversely correlated with fluid indices. Multiple cytokines, including ANGPTL4, were directly correlated with ellipsoid zone disruption. The baseline VEGF levels were significantly higher in all responders compared to Non-Responders (p = 0.02). Rebounders tended to have significantly decreased levels of angiogenin and TIMP-1 (p = 0.019, p = 0.015).

    Conclusions: Cytokine expression was linked to specific OCT features and treatment response in RVO. Identification of an imaging phenotype that could serve as a surrogate for underlying active disease pathways could enhance treatment decision-making and precision medicine.

    DOI: 10.1038/s41433-022-02265-2

    Structural Features of Patients with Drusen-like Deposits and Systemic Lupus Erythematosus.

    Journal of Clinical Medicine. 2022 Oct 12

    Kukan M, Driban M, Vupparaboina KK, Schwarz S, Kitay AM, Rasheed MA, Busch C, Barthelmes D, Chhablani J, Al-Sheikh M.

    Background: The relevance of drusen-like deposits (DLD) in patients with systemic lupus erythematosus (SLE) is to a large extent uncertain. Their genesis is proposed to be correlated to immune-complex and complement depositions in the framework of SLE. The intention of this study was to determine potential morphological differences in the choroid and retina as well as potential microvascular changes comparing two cohorts of SLE patients divergent in the presence or absence of DLD using multimodal imaging.

    Methods: Both eyes of 16 SLE patients with DLD were compared to an age- and sex-matched control-group consisting of 16 SLE patients without detectable DLD. Both cohorts were treated with hydroxychloroquine (HCQ) and did not differ in the treatment duration or dosage. Using spectral-domain optical coherence tomography (SD-OCT) choroidal volume measures, choroidal vascularity indices (CVI) and retinal layer segmentation was performed and compared. In addition, by the exploitation of optical coherence tomography angiography vascular density, perfusion density of superficial and deep retinal capillary plexuses and the choriocapillaris were analyzed. For the choroidal OCT-scans, a subset of 51 healthy individuals served as a reference-group.

    Results: CVI measures revealed a significant reduction in eyes with DLD compared to healthy controls (0.56 (0.54-0.59) versus 0.58 (0.57-0.59) (p = 0.018) and 0.56 (0.54-0.58) versus 0.58 (0.57-0.60) (p < 0.001)). The photoreceptor cell layer presented significant thinning in both eyes of subjects with DLD compared to control subjects without DLD (68.8 ± 7.7 µm vs. 77.1 ± 7.3 µm for right eyes, p = 0.008, and 66.5 ± 10.5 µm vs. 76.1 ± 6.3 µm for left eyes, p = 0.011). OCTA scans revealed no significant changes, yet there could be observed numerically lower values in the capillary plexuses of the retina in eyes with DLD than in eyes without DLD.

    Conclusions: Our results illustrated significant alterations in the choroidal and retinal analyzes, suggesting a correlation between DLD and the progression of inflammatory processes in the course of SLE leading to retinal degeneration. For this reason, DLD could serve as a biomarker for a more active state of disease.

    DOI: 10.3390/jcm11206012


    Long-Term Retinal Vascular Changes in Age-Related Macular Degeneration Measured Using Optical Coherence Tomography Angiography.

    Ophthalmic Surgery, Lasers & Imaging Retina. 2022 Oct

    Lee SC, Rusakevich AM, Amin A, Tran S, Emami-Naeini P, Moshiri A, Park SS, Yiu G.

    Background and objective: To determine if age-related macular degeneration (AMD) status affects longitudinal retinal vessel changes.

    Patients and methods: Retrospective, cohort study of 125 eyes (75 patients) with AMD, following retinal vessel density (VD) and foveal avascular zone (FAZ) measurements using optical coherence tomography angiography (OCT-A) over 24 months.

    Results: FAZ area (P < .001) and perimeter (P < .001) increased over 2 years, with no difference between nonexudative and exudative AMD (P = .134-.976). Eyes with geographic atrophy (GA) showed greater progressive VD loss (P = .023-.038), and greater increase in FAZ area (P = .044) and perimeter (P = .040) compared to eyes without GA. Neither baseline nor 2-year change in vascular parameters were associated with choroidal neovascularization (CNV) or GA incidence in nonexudative AMD, or anti-VEGF injection frequency in exudative AMD (P = .070-.952).

    Conclusion: AMD eyes with GA undergo more rapid loss of retinal vessel density and FAZ enlargement over 2 years, suggesting a relationship between the retinal vasculature and AMD pathophysiology. [Ophthalmic Surg Lasers Imaging Retina 2022;53:529-536.].

    DOI: 10.3928/23258160-20220919-01

    Pachychoroid neovasculopathy can mimic wet type age-related macular degeneration.

    International Journal of Retina and Vitreous. 2022 Oct 23

    Farvardin M, Amini A, Azizpourfard Y, Yasemi M, Mahdizad Z, Johari M.

    Purpose: to determine the percentage of patients with pachychoroid neovasculopathy (PNV) among patients who have been misdiagnosed and treated with wet age-related macular degeneration (AMD).

    Methods: In this retrospective cross-sectional study, patients over 55 years old, who were diagnosed with wet AMD, were re-evaluated. All patients were recalled for examination and imaging. Patients with PNV were differentiated form wet AMD based on inclusion and exclusion criteria.

    Results: Overall, 120 patients (137 eyes) were recorded with wet AMD in the clinic. Finally, after complete re-evaluation, 94 (106 eyes) and 26 patients (31 eyes) were assigned to the AMD and the PNV group, respectively. Thus, a total of 20% of patients with primary mistake diagnosis of wet AMD, actually had PNV. The mean sub field choroidal thickness (SFCT) in the AMD and PNV groups was 173.8 ± 69 μm and 342 ± 27 μm, respectively. Drusen and pachydrusen were found in 69.9% and 24% of the cases with AMD and PNV, respectively (P = 0.001). The average number of intravitreal injections of anti-VEGF (vascular endothelial growth factor) required in the AMD and PNV groups was about 5 and 3, respectively, which was statistically significant (P-value 0.02).

    Conclusion: This study revealed that about a one-fifth of wet AMD patients are actually pachychoroid neovasculopathy. These patients were younger and had thicker SFCT, and developed less subretinal scarring. Thus, the disorder must be considered as an important differential diagnosis of AMD-CNV.

    DOI: 10.1186/s40942-022-00429-6

    Retinal nerve fiber layer in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

    Frontiers in Neuroscience. 2022 Oct 6

    Wong BM, Hudson C, Snook E, Tayyari F, Jung H, Binns MA, Samet S, Cheng RW, Balian C, Mandelcorn ED, Margolin E, Finger E, Black SE, Tang-Wai DF, Zinman L, Tan B, Lou W, Masellis M, Abrahao A, Frank A, Beaton D, Sunderland KM, Arnott SR; ONDRI Investigators, Tartaglia MC, Hatch WV.

    Purpose: Tauopathy and transactive response DNA binding protein 43 (TDP-43) proteinopathy are associated with neurodegenerative diseases. These proteinopathies are difficult to detect in vivo. This study examined if spectral-domain optical coherence tomography (SD-OCT) can differentiate in vivo the difference in peripapillary retinal nerve fibre layer (pRNFL) thickness and macular retinal thickness between participants with presumed tauopathy (progressive supranuclear palsy) and those with presumed TDP-43 proteinopathy (amyotrophic lateral sclerosis and semantic variant primary progressive aphasia).

    Study design: Prospective, multi-centre, observational study.

    Materials and methods: pRNFL and macular SD-OCT images were acquired in both eyes of each participant using Heidelberg Spectralis SD-OCT. Global and pRNFL thickness in 6 sectors were analyzed, as well as macular thickness in a central 1 mm diameter zone and 4 surrounding sectors. Linear mixed model methods adjusting for baseline differences between groups were used to compare the two groups with respect to pRNFL and macular thickness.

    Results: A significant difference was found in mean pRNFL thickness between groups, with the TDP-43 group (n = 28 eyes) having a significantly thinner pRNFL in the temporal sector than the tauopathy group (n = 9 eyes; mean difference = 15.46 μm, SE = 6.98, p = 0.046), which was not significant after adjusting for multiple comparisons. No other significant differences were found between groups for pRNFL or macular thickness.

    Conclusion: The finding that the temporal pRNFL in the TDP-43 group was on average 15.46 μm thinner could potentially have clinical significance. Future work with larger sample sizes, longitudinal studies, and at the level of retinal sublayers will help to determine the utility of SD-OCT to differentiate between these two proteinopathies.

    DOI: 10.3389/fnins.2022.964715


    Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy.

    Ophthalmology Science. 2022 Mar 16

    Yanagi Y, Yu RMC, Ahamed W, Yu M, Teo KYC, Tan ACS, Cheng CY, Wong TY, Apte RS, Cheung CMG.

    Purpose: To investigate serum cholesterol efflux capacity (the ability of the serum to accept cholesterol) and factors that regulate it using nuclear magnetic resonance-quantified measures of lipoprotein particle composition and size and apolipoproteins metrics in patients with age-related macular degeneration (AMD). DESIGN: Case-control study.

    Participants: Four hundred two serum samples from 80 patients with early AMD (eAMD), and 212 patients with neovascular AMD (nAMD), including 80 with typical nAMD (tAMD) and 132 with polypoidal choroidal vasculopathy (PCV), and 110 age- and gender matched control participants.

    Methods: Serum from participants showed cholesterol efflux capacity measured using in vitro cell assays and lipoprotein subfractions measured using nuclear magnetic resonance (Nightingale, Ltd). Associations between cholesterol efflux capacity (measured in percentage) and lipid subfractions were investigated in the patients and control participants.

    Main outcome measures: Cholesterol efflux capacity and lipid subfractions in control, eAMD, and nAMD. Associations between HDL subfractions and cholesterol efflux capacity. RESULTS: Cholesterol efflux capacity was higher in patients with eAMD (68.0 ± 11.3% [mean ± standard deviation]) and nAMD (75.9 ± 27.7%) than in the control participants (56.9 ± 16.7%) after adjusting for age, gender, and use of lipid-lowering drug (P < 0.0001). Nuclear magnetic resonance lipidomics demonstrated that the mean diameter of HDL was larger both in eAMD (9.96 ± 0.27 mm [mean ± standard deviation]) and PCV (9.97 ± 0.23 mm) compared with that of the control participants (9.84 ± 0.24 mm; P = 0.0001 for both). Among the 28 HDL subfractions, most of the small, medium, and large HDLs, but none of the 7 extra large HDLs fractions, were associated moderately with cholesterol efflux capacity in eAMD and PCV (R = 0.149-0.277).

    Conclusions: Serum cholesterol efflux capacity was increased in eAMD and PCV, but not tAMD, possibly reflecting differential underlying pathophysiologic features of lipid dysregulation in tAMD and PCV. Further studies should be directed toward investigating the diverse biological activities of HDL in AMD, including macular pigment transport, regulation of inflammation, and local cholesterol transport system.

    DOI: 10.1016/j.xops.2022.100142