Dataset Information

Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys.

ABSTRACT: The retina is an ideal target for gene therapy because of its easy accessibility and limited immunological response. We previously reported that intravitreally injected adeno-associated virus (AAV) vector transduced the inner retina with high efficiency in a rodent model. In large animals, however, the efficiency of retinal transduction was low, because the vitreous and internal limiting membrane (ILM) acted as barriers to transduction. To overcome these barriers in cynomolgus monkeys, we performed vitrectomy (VIT) and ILM peeling before AAV vector injection. Following intravitreal injection of 50 ?L triple-mutated self-complementary AAV serotype 2 vector encoding EGFP, transduction efficiency was analyzed. Little expression of GFP was detected in the control and VIT groups, but in the VIT+ILM group, strong GFP expression was detected within the peeled ILM area. To detect potential adverse effects, we monitored the retinas using color fundus photography, optical coherence tomography, and electroretinography. No serious side effects associated with the pretreatment were observed. These results indicate that surgical ILM peeling before AAV vector administration would be safe and useful for efficient transduction of the nonhuman primate retina and provide therapeutic benefits for the treatment of retinal diseases.

SUBMITTER: Takahashi K

PROVIDER: S-EPMC5363307 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys.

Takahashi Kazuhisa K Igarashi Tsutomu T Miyake Koichi K Kobayashi Maika M Yaguchi Chiemi C Iijima Osamu O Yamazaki Yoshiyuki Y Katakai Yuko Y Miyake Noriko N Kameya Shuhei S Shimada Takashi T Takahashi Hiroshi H Okada Takashi T

Molecular therapy : the journal of the American Society of Gene Therapy 20170104 1

The retina is an ideal target for gene therapy because of its easy accessibility and limited immunological response. We previously reported that intravitreally injected adeno-associated virus (AAV) vector transduced the inner retina with high efficiency in a rodent model. In large animals, however, the efficiency of retinal transduction was low, because the vitreous and internal limiting membrane (ILM) acted as barriers to transduction. To overcome these barriers in cynomolgus monkeys, we perfor ...[more]

PMID: 28129123

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Project description:BackgroundEpiretinal membranes (ERMs) have been reported after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD). Peeling of the internal limiting membrane (ILM) can prevent post-PPV ERM formation but has a potential negative impact on macular structure and function.PurposeTo investigate the anatomical and functional outcomes of ILM peeling during PPV for primary RRD.MethodsThis was a prospective nonrandomized study that included 60 eyes of 60 patients with a primary macula-off RRD and less than grade C proliferative vitreoretinopathy (PVR). Eyes were allocated into 2 groups; Group A underwent PPV without ILM peeling and Group B had ILM peeling. At postoperative month 6, all patients underwent retinal imaging using spectral domain optical coherence tomography (OCT) and OCT angiography and macular function was assessed using multifocal electroretinogram (mfERG). Baseline characteristics and postoperative anatomical and visual outcomes were recorded and statistically analyzed.ResultsWe enrolled 30 eyes of 30 patients in each group. In Group A, mean age was 44.6 years, while the mean age of Group B patients was 49.9 years. Postoperative LogMAR visual acuity was significantly better in Group A than in Group B (p < 0.001). ERMs were demonstrated on OCT in 13.3% of Group A and none of Group B patients (p = 0.04). Retinal dimples were found in 53.3% of Group B and none of Group A eyes (p < 0.001). OCTA showed a greater vessel density of the superficial capillary plexus (SCP) in Group A compared to Group B eyes (p = 0.046), while no difference was found regarding deep capillary vessel density (p = 0.7). Mean amplitude of mfERG P1 wave was significantly higher in Group A eyes than in Group B (p = 0.002). Both the SCP vessel density and P1 amplitude were positively correlated with visual acuity (p < 0.001).ConclusionThis study suggests that ILM peeling prevents ERM development in eyes undergoing PPV for uncomplicated macula-off RRD, but potential damage to macular structure and function were found.Trial registration Retrospectively registered on 09/24/2019 on ClinicalTrials.gov with an ID of NCT04139811.

Project description:BackgroundInternal limiting membrane (ILM) peeling during primary vitrectomy for rhegmatogenous retinal detachment (RRD) prevents the formation of postoperative macular epiretinal membrane (ERM). However, studies that compared vitrectomy with and without ILM peeling for RRD, have reported controversial outcomes.ObjectiveTo assess the efficacy of ILM peeling versus non-ILM peeling during vitrectomy for RRD by a systematic review and meta-analysis of published studies.MethodsPubMed, Medline, Web of Science, Embase databases, and the Cochrane Library were searched up to April 2018 to identify studies that compared primary vitrectomy with and without ILM peeling for RRD with at least six months follow-up. Primary outcomes were the rate of postoperative ERM formation and mean best corrected visual acuity (BCVA) change after vitrectomy. Rate of recurrence of retinal detachment (RD) was assessed as secondary outcome. Risk ratios (RRs) with 95% confidence intervals (CIs) expressed pooled results for rate of ERM formation and rate of RD recurrence in ILM peeling and non-ILM peeling groups. Pooled results for BCVA change in the two groups were expressed as Weighted Mean Difference (WMD) with 95% CIs.ResultsNine studies, one of which was a randomized controlled trial (RCT), with a total number of 404 eyes in the ILM peeling group and 365 eyes in the non-ILM peeling group, were included. The analysis from pooled data indicated a significant lower rate of postoperative ERM formation in the ILM peeling group compared to the non-ILM peeling group (9 studies, 769 eyes, RR = 0.14; CI: 0.07 to 0.28; P < 0.001). There was no statistical difference in mean BCVA change (9 studies, 769 eyes, WMD = 0.02; CI: -0.11 to 0.16; P = 0.75). Rate of recurrence of RD was lower in the ILM peeling group (6 studies, 603 eyes, RR = 0.32; CI = 0.17 to 0.61; P< 0.001).ConclusionILM peeling during vitrectomy for RRD prevents the formation of macular epiretinal membrane postoperatively and reduces the incidence of RD recurrence, but better visual outcome was not found compared to non-ILM peeling vitrectomy.

Dataset Information

Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys.

Publications

Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys.

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