RESUMO
PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.
Assuntos
Neovascularização de Coroide/cirurgia , Fotocoagulação a Laser/métodos , Drusas Retinianas/cirurgia , Degeneração Macular Exsudativa/cirurgia , Idoso , Neovascularização de Coroide/diagnóstico por imagem , Neovascularização de Coroide/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Drusas Retinianas/diagnóstico por imagem , Drusas Retinianas/fisiopatologia , Fatores de Risco , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/diagnóstico por imagem , Degeneração Macular Exsudativa/fisiopatologiaRESUMO
IMPORTANCE: Improved vision self-monitoring tools are required for people at risk of neovascular complications from age related macular degeneration (AMD). BACKGROUND: to report the self-monitoring habits of participants with intermediate AMD using the Amsler grid chart, and the use of personal electronic devices and gameplay in this over 50 year old cohort. DESIGN: single-centre descriptive study carried out at the Centre for Eye Research (CERA), Melbourne, Australia. PARTICIPANTS: 140 participants over 50 years of age, with a diagnosis of intermediate AMD and best-corrected visual acuity (BCVA) of ≥6/12 in each eye. METHODS: structured questionnaire survey of participants who were enrolled in natural history of AMD studies at CERA. MAIN OUTCOME MEASURES: frequency of vision self-monitoring using the Amsler grid chart, and frequency of general use of personal electronic devices and gameplay. RESULTS: Of 140 participants with mean age of 70.5 years, 83.6% used an Amsler grid chart, but only 39.3% used it once per week. Most participants (91.4%) used one or more personal electronic devices. Of these, over half (54.7%) played games on them, among whom 39% played games once a day. Of participants aged 50-69 years, 92% (95%CI 85.1-98.9) were willing to play a game to monitor their vision, compared to 78% (95%CI 69.0-87.0) of those aged 70 years and older (P < 0.05). CONCLUSIONS AND RELEVANCE: a large proportion of AMD patients already use personal electronic devices. Gamification techniques are likely to increase compliance with self-monitoring, leading to earlier detection in the next generation of patients with neovascular AMD.
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Monitorização Fisiológica/métodos , Autocuidado/métodos , Jogos de Vídeo , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/reabilitação , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Inquéritos e Questionários , Testes de Campo Visual , Degeneração Macular Exsudativa/fisiopatologiaRESUMO
PURPOSE: The ARMS2/HTRA1 genes at the 10q26 locus have been associated with risk of age-related macular degeneration (AMD), with the most significantly associated variants being A69S (rs10490924), del443ins54 (EU427539) and rs11200638. We wished to explore the association of the del443ins54 in two ethnically different populations from India and Australia. METHODS: The del443ins54 was screened in a large cohort of ~1500 subjects from these two populations by a combination of PCR-based agarose gel electrophoresis and validated by resequencing. Statistical analysis comprised the calculations of allele, genotype and haplotype frequencies along with their p values and corresponding odds ratios (OR), and 95% confidence intervals (95% CI) and measures of linkage disequilibrium (LD). RESULTS: The del443ins54 was significantly associated with AMD in both the Indian (p=1.74 × 10(-13); OR = 2.80, 95%CI, 2.12-3.70) and Australian cohorts (p = 2.78 × 10(-30); OR = 3.15, 95%CI, 2.58-3.86). These associations were similar to those previously identified for the A69S and the rs11200638 variant in these populations that also exhibited high degrees of LD (D' of 0.87-0.99). A major risk haplotype of "T-indel-A" (p = 5.7 × 10(-16); OR = 3.16, 95%CI, 2.34-4.19 and p=6.33 × 10(-30); OR = 3.15, 95%CI, 2.57-3.85) and a protective haplotype of "G-wild type-G" (p=2.35 × 10(-11); OR = 0.39, 95%CI, 0.29-0.52 and p=1.02 × 10(-30); OR = 0.31, 95%CI, 0.25-0.38) were identified in the Indian and Australian cohorts, respectively. CONCLUSIONS: These data provide an independent replication of the association of del443ins54 variant in two different ethnicities, despite differences in allele and haplotype frequencies between them. High levels of LD in both populations limit further genetic dissection of this region in AMD.
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Estudos de Associação Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Mutação INDEL/genética , Degeneração Macular/genética , Proteínas/genética , Austrália , Estudos de Coortes , Frequência do Gene/genética , Haplótipos/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Índia , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Serina Endopeptidases/genéticaRESUMO
INTRODUCTION: Voretigene neparvovec-rzyl (Luxturna) was approved by the Australian Therapeutic Goods Administration on 4 August 2020 for the treatment of biallelic mutations in the RPE65 gene, a rare cause of congenital and adult-onset retinal dystrophy (predominantly Leber congenital amaurosis). Previous studies have shown that individuals who might participate in gene therapy trials overestimate clinical effect and underestimate risks. However, little is known about the perspectives of patients who may be offered approved gene therapy treatment for ocular conditions (as distinct from participating in clinical trials of gene therapy). The main objective of this study is to develop a tool to assess knowledge, attitudes and perceptions of approved and future genetic therapies among potential recipients of ocular gene therapy. In addition, we aim to assess the quality of life, attitudes towards clinical trials and vision-related quality of life among this cohort. METHODS AND ANALYSIS: A new 'Attitudes to Gene Therapy for the Eye' tool will be developed following consultation with people with inherited retinal disease (IRD) and content matter experts. Australians with IRD or their guardians will be asked to complete an internet-based survey comprising existing quality of life and visual function instruments and items for the newly proposed tool. We expect to recruit 500 survey participants from patient support groups, the practices of Australian ophthalmologists who are specialists in IRD and Australian ophthalmic research institutions. Launch is anticipated early 2021. Responses will be analysed using item response theory methodology. ETHICS AND DISSEMINATION: This study has received ethics approval from the University of Melbourne (#2057534). The results of the study will be published in a peer-reviewed journal and will be presented at relevant conferences. Organisations involved in recruitment, and the Patient Engagement Advisory committee will assist the research team with dissemination of the study outcomes.
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Amaurose Congênita de Leber , Doenças Retinianas , Adulto , Austrália , Terapia Genética , Humanos , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/terapia , Qualidade de VidaRESUMO
PURPOSE: To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD). DESIGN: Observational extension study of a randomized, sham-controlled trial. PARTICIPANTS: Two hundred twelve participants with bilateral large drusen. METHODS: The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data. MAIN OUTCOME MEASURES: Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment. RESULTS: Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36-1.09; P = 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P = 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16-0.71; P = 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67-4.88; P = 0.239). CONCLUSIONS: A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.
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Angiofluoresceinografia/métodos , Terapia a Laser/métodos , Degeneração Macular/cirurgia , Imagem Multimodal/métodos , Drusas Retinianas/cirurgia , Idoso , Progressão da Doença , Feminino , Fundo de Olho , Humanos , Degeneração Macular/complicações , Degeneração Macular/diagnóstico , Masculino , Drusas Retinianas/diagnóstico , Drusas Retinianas/etiologia , Fatores de Risco , Resultado do TratamentoRESUMO
PURPOSE: Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP). DESIGN: Prospective, longitudinal, observational study. PARTICIPANTS: A total of 284 eyes from 142 participants with bilateral large drusen and without nGA nor late age-related macular degeneration (AMD) at baseline were included. METHODS: OCT volume scans and CFP images were obtained from all participants at baseline and then at 6-month intervals for up to 36 months. OCT and CFP images were graded independently for the presence of nGA and GA, respectively. Eyes that developed neovascular AMD were censored at the day of its detection. MAIN OUTCOME MEASURES: Time to development of GA. RESULTS: A total 12 eyes from 10 participants progressed to GA over 36 months of follow-up, and nGA was detected in 10 of these eyes (83%) at a preceding visit (median, 13 months prior; interquartile range, 6-25 months). A total of 40 eyes from 28 participants developed nGA or GA over 36 months of follow-up, and the probability of progression to nGA and GA after 36 months was 20% (95% confidence interval [CI], 14%-28%) and 9% (95% CI, 6%-13%), respectively. After the detection of nGA, the probability of progression to GA was 38% (95% CI, 15%-55%) after 24 months. The development of nGA was associated with a markedly increased risk of progression to GA compared with when it did not develop (adjusted hazard ratio, 78.1; 95% CI, 13.6-448.0; P < 0.001), and the development of nGA explained 91% of the variance in the time to GA development. CONCLUSIONS: This study prospectively demonstrated that nGA was a strong predictor for the development of GA, providing supportive evidence of the potential value of nGA as a surrogate endpoint in future intervention trials for the early stages of AMD to improve their feasibility substantially.
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Atrofia Geográfica/etiologia , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica/métodos , Degeneração Macular Exsudativa/complicações , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Atrofia Geográfica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Degeneração Macular Exsudativa/diagnósticoRESUMO
PURPOSE: To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages. DESIGN: Multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two-hundred ninety-two patients with bilateral large drusen. METHODS: Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals. MAIN OUTCOME MEASURES: The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non-study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non-study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire. RESULTS: Progression to late AMD in the non-study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40-1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non-study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (-0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non-study eye (-0.48 and -0.56 letters/year, respectively; P = 0.628). CONCLUSIONS: Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.
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Terapia a Laser/métodos , Degeneração Macular/cirurgia , Drusas Retinianas/cirurgia , Acuidade Visual , Idoso , Idoso de 80 Anos ou mais , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Macula Lutea/patologia , Degeneração Macular/complicações , Degeneração Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Drusas Retinianas/diagnóstico , Drusas Retinianas/etiologia , Resultado do TratamentoRESUMO
The Alliance for Cellular Signaling (AfCS)-Nature Molecule Pages will be a comprehensive database of key facts about more than 3,000 proteins involved in cell signalling. Each entry will be created by invited experts and be peer-reviewed. Alongside the large-scale experiments being conducted by the AfCS scientists, the wealth of information contained in this database offers the potential of accelerating the pace of discovery in signal transduction research.