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Translational Vision Science &... Nov 2023This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). (Meta-Analysis)
Meta-Analysis
PURPOSE
This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV).
METHODS
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1.
RESULTS
Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%).
CONCLUSIONS
AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up.
TRANSLATIONAL RELEVANCE
This systematic review will help to inform and guide future clinical trials.
Topics: Humans; Retinal Degeneration; Dependovirus; Macular Degeneration; Retinitis Pigmentosa; Genetic Therapy
PubMed: 37982768
DOI: 10.1167/tvst.12.11.24 -
Genetics in Medicine : Official Journal... Mar 2022This study aimed to systematically review and summarize gene therapy treatment for monogenic retinal and optic nerve diseases. (Review)
Review
PURPOSE
This study aimed to systematically review and summarize gene therapy treatment for monogenic retinal and optic nerve diseases.
METHODS
This review was prospectively registered (CRD42021229812). A comprehensive literature search was performed in Ovid MEDLINE, Ovid Embase, Cochrane Central, and clinical trial registries (February 2021). Clinical studies describing DNA-based gene therapy treatments for monogenic posterior ocular diseases were eligible for inclusion. Risk of bias evaluation was performed. Data synthesis was undertaken applying Synthesis Without Meta-analysis guidelines.
RESULTS
This study identified 47 full-text publications, 50 conference abstracts, and 54 clinical trial registry entries describing DNA-based ocular gene therapy treatments for 16 different genetic variants. Study summaries and visual representations of safety and efficacy outcomes are presented for 20 unique full-text publications in RPE65-mediated retinal dystrophies, choroideremia, Leber hereditary optic neuropathy, rod-cone dystrophy, achromatopsia, and X-linked retinoschisis. The most common adverse events were related to lid/ocular surface/cornea abnormalities in subretinal gene therapy trials and anterior uveitis in intravitreal gene therapy trials.
CONCLUSION
There is a high degree of variability in ocular monogenic gene therapy trials with respect to study design, statistical methodology, and reporting of safety and efficacy outcomes. This review improves the accessibility and transparency in interpreting gene therapy trials to date.
Topics: Color Vision Defects; Genetic Therapy; Humans; Optic Nerve Diseases; Retina; Retinal Dystrophies
PubMed: 34906485
DOI: 10.1016/j.gim.2021.10.013 -
International Journal of Molecular... Jan 2024X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with... (Review)
Review
X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE's risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.
Topics: Male; Humans; Animals; Mice; Retinoschisis; Retina; Electroretinography; Genetic Therapy; Mutation; Eye Proteins
PubMed: 38279267
DOI: 10.3390/ijms25021267 -
Eye (London, England) Oct 2020X-linked retinoschisis (XLRS) is a leading cause of hereditary juvenile macular degeneration in males resulting in significant vision impairment. Outcome measures to... (Review)
Review
X-linked retinoschisis (XLRS) is a leading cause of hereditary juvenile macular degeneration in males resulting in significant vision impairment. Outcome measures to monitor disease progression or therapeutic interventions have evolved with technology. A systematic review was undertaken to evaluate outcome measures for XLRS. Inclusion criteria were all publications examining outcome measures for natural history studies or following an interventional approach for patients with XLRS. Studies which did not present follow-up data were excluded. We searched medical databases including CENTRAL, Ovid Medline, pre-Medline and ahead of Print up to February 2019. Two authors independently assessed the risk of bias. Twelve studies meet the inclusion criteria with four prospective and eight retrospective case series. Five series were natural history observational studies and seven were interventional series using either topical or systemic carbonic anhydrase inhibitors. Visual acuity (VA) declined very slowly in the natural history studies equivalent to 0.22-0.5 letters per year. Five of the six interventional studies showed an improvement in VA and four a reduction in spectral domain optical coherence tomography (SD-OCT) parameters for central macular thickness (CMT). The full-field electroretinogram identified the 30-Hz latency as a further parameter to monitor function. VA was the measure most likely to show a statistically significant outcome. How functionally meaningful this is, requires further evaluation. CMT SD-OCT outcomes are variable depending on cystic changes. More refined measures are required to better correlate structure with function.
Topics: Humans; Male; Outcome Assessment, Health Care; Prospective Studies; Retinoschisis; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity
PubMed: 32313171
DOI: 10.1038/s41433-020-0848-6 -
BMC Ophthalmology Sep 2017Myopic foveoschisis (MF) is among the leading causes of visual loss in high myopia. However, it remains controversial whether internal limiting membrane (ILM) peeling or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Myopic foveoschisis (MF) is among the leading causes of visual loss in high myopia. However, it remains controversial whether internal limiting membrane (ILM) peeling or gas tamponade is necessary treatment option for MF.
METHODS
PubMed, EMBASE, CBM, CNKI, WANFANG DATA and VIP databases were systematically reviewed. Outcome indicators were myopic foveoschisis resolution rate, visual acuity improvement and postoperative complications.
RESULTS
Nine studies that included 239 eyes were selected. The proportion of resolution of foveoschisis was higher in ILM peeling group than non-ILM peeling group (OR = 2.15, 95% CI: 1.06-4.35; P = 0.03). The proportion of postoperative complications was higher in Tamponade group than non-Tamponade group (OR = 10.81, 95% CI: 1.26-93.02; P = 0.03). However, the proportion of visual acuity improvement (OR = 1.63, 95% CI: 0.56-4.80; P = 0.37) between ILM peeling group and non-ILM peeling group and the proportion of resolution of foveoschisis (OR = 1.80, 95% CI: 0.76-4.28; P = 0.18) between Tamponade group and non-Tamponade group were similar.
CONCLUSIONS
Vitrectomy with internal limiting membrane peeling could contribute to better resolution of myopic foveoschisis than non-peeling, however it does not significantly influence the proportion of visual acuity improvement and postoperative complications. Vitrectomy with gas tamponade is associated with more complications than non-tamponade and does not significantly influence the proportion of visual acuity improvement and resolution of myopic foveoschisis.
Topics: Basement Membrane; Endotamponade; Humans; Myopia, Degenerative; Retinoschisis; Vitrectomy
PubMed: 28886700
DOI: 10.1186/s12886-017-0562-8 -
Acta Ophthalmologica Nov 2021To evaluate the basic characteristics of optic disc pit maculopathy (ODPM) and the efficacies of pars plana vitrectomy (PPV) treatment with different adjunctive... (Meta-Analysis)
Meta-Analysis
PURPOSE
To evaluate the basic characteristics of optic disc pit maculopathy (ODPM) and the efficacies of pars plana vitrectomy (PPV) treatment with different adjunctive strategies.
METHODS
The databases PubMed, EMBASE and Ovid up to April 2020 were searched to identify relevant studies. Statistical analyses were conducted with R software version 3.6.3.
RESULTS
Fifty-nine studies were eventually included for different aspects of statistical analyses. The pooling results suggest the general incidence of maculopathy in optic disc pit (ODP) is 51%, and the rate of serous macular detachment and retinoschisis is 49% and 58%, respectively. The incidence of sub-retinal fluid (SRF) only is 10%, intra-retinal retinal (IRF) fluid only is 14%, and SRF plus IRF is 69%. A lamellar macular hole (LMH) is present in 53% of cases, and 58% have communication between the macula with the pit. The incidence of posterior vitreous detachment (PVD), vitreo-papillary traction and vitreomacular traction (VMT) is 7%, 28% and 13%, respectively. Besides, the rate of complete anatomic success and visual improvement after PPV are both around 85%. Subgroup analysis reveals the anatomic, and visual success rates of PPV alone are 89% and 100%, respectively. Gas tamponade, laser or internal limiting membrane peeling (ILMP) during vitrectomy are less promising, while PPV with ILM flap stuffing could achieve better outcomes than cases without it.
CONCLUSION
Optic disc pit-associated maculopathy has different fundus characteristics. Based on the current evidence, PPV is effective for ODPM, and the combined application of gas tamponade, laser and ILMP should be used with caution.
Topics: Eye Abnormalities; Humans; Macular Degeneration; Optic Disk; Tomography, Optical Coherence; Vitrectomy
PubMed: 33421324
DOI: 10.1111/aos.14730 -
Retina (Philadelphia, Pa.) Jun 2021To evaluate fovea-sparing internal limiting membrane (ILM) peeling in vitrectomy compared with traditional complete ILM peeling in vitreomacular interface diseases,... (Meta-Analysis)
Meta-Analysis
PURPOSE
To evaluate fovea-sparing internal limiting membrane (ILM) peeling in vitrectomy compared with traditional complete ILM peeling in vitreomacular interface diseases, including macular hole (MH), epiretinal membrane, macular foveoschisis, myopic traction maculopathy, and the like.
METHODS
PubMed, EMBASE, Cochrane, CNKI Databases, and the ClinicalTrials.gov website (PROSPERO number CRD42020187401) were searched. Controlled trials comparing fovea-sparing with complete ILM peeling were included. Postoperative changes in best-corrected visual acuity, central retinal thickness in vitreomacular interface diseases, the incidence of MH closure in MH cases, full-thickness macular hole development in non-MH cases, and retinal reattachment in retinoschisis cases were extracted.
RESULTS
Fourteen studies (487 eyes) were eligible. Compared with complete ILM peeling, the fovea-sparing technique revealed significant improvement in best-corrected visual acuity ( logarithm of the minimum angle of resolution; weighted mean difference = -0.70; 95% confidence interval, -1.11 to -0.30), and a reduced incidence of full-thickness macular hole was noted in non-MH cases (risk ratios = 0.25; 95% confidence interval, 0.08-0.76). However, no significant differences in mean change in central retinal thickness, incidence of MH closure in MH cases, and retinal reattachment in retinoschisis cases were noted.
CONCLUSION
Based on current evidence, fovea-sparing ILM peeling significantly improve visual outcomes and decrease complications of full-thickness macular hole development in vitreomacular interface diseases.
Topics: Basement Membrane; Fovea Centralis; Humans; Retinal Diseases; Tomography, Optical Coherence; Visual Acuity; Vitrectomy
PubMed: 34001832
DOI: 10.1097/IAE.0000000000003140 -
Ophthalmic Research 2021Myopic traction maculopathy (MTM) is a major cause of impaired vision in eyes with high myopia, which is characterized by retinal thickening, retinoschisis, lamellar... (Comparative Study)
Comparative Study Meta-Analysis
INTRODUCTION
Myopic traction maculopathy (MTM) is a major cause of impaired vision in eyes with high myopia, which is characterized by retinal thickening, retinoschisis, lamellar macular hole (MH), and foveal retinal detachment. Pars plana vitrectomy (PPV) with fovea-sparing internal limiting membrane peeling (ILMP) has been developed to theoretically prevent postoperative MH formation and improve best-corrected visual acuity (BCVA) gain for MTM compared with the complete ILMP. However, in previous studies, the anatomic and visual outcomes still remain uncertain and controversial.
OBJECTIVES
The aim of this study was to evaluate the anatomic and visual outcomes of vitrectomy with fovea-sparing ILMP for the treatment of MTM compared with complete ILMP.
METHODS
Articles from PubMed, EMBASE, Web of Science, and Cochrane Library were systematically retrieved. The main outcomes were the rate of a postoperative MH and visual improvement of BCVA (converted to logarithm of the minimum angle of resolution [logMAR]). The secondary outcomes were the proportion of patients with visual improvement, the proportion of anatomic success, preoperative and postoperative BCVA, preoperative and postoperative central fovea thickness, and time to anatomic resolution.
RESULTS
There was a higher rate of postoperative MH formation (odds ratio [OR] 5.64; 95% confidence interval [CI]: 1.72-18.44; p = 0.004) and less improvement of BCVA in logMAR (mean difference [MD] -0.09; 95% CI: -0.18 to 0.00; p = 0.04) in the complete ILMP group. However, postoperative BCVA (MD 0.14; 95% CI: 0.00-0.27; p = 0.05), the proportion of patients with visual improvement (OR 0.39; 95% CI: 0.15-1.02; p = 0.05), postoperative central foveal thickness (MD -10.02; 95% CI: -24.4 to 4.36; p = 0.17), the rate of anatomic success (MD 0.39; 95% CI: 0.15-1.03; p = 0.06), and time to resolution (MD -1.65; 95% CI: -3.66 to 0.36; p = 0.11) showed no significant differences.
CONCLUSION
PPV combined with the fovea-sparing ILMP could contribute to a lower MH formation rate and more improvement of BCVA in logMAR than PPV combined with complete ILMP.
Topics: Basement Membrane; Humans; Macular Degeneration; Myopia, Degenerative; Retinal Perforations; Retrospective Studies; Tomography, Optical Coherence; Traction; Visual Acuity; Vitrectomy
PubMed: 34425571
DOI: 10.1159/000519021