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Co-Injection of Sulfotyrosine Facilitates Retinal Uptake of Hyaluronic Acid Nanospheres Following Intravitreal Injection.

ABSTRACT: Gene and drug delivery to the retina is a critical therapeutic goal. While the majority of inherited forms of retinal degeneration affect the outer retina, specifically the photoreceptors and retinal pigment epithelium, effective targeted delivery to this region requires invasive subretinal delivery. Our goal in this work was to evaluate two innovative approaches for increasing both the persistence of delivered nanospheres and their penetration into the outer retina while using the much less invasive intravitreal delivery method. We formulated novel hyaluronic acid nanospheres (HA-NS, 250 nm and 500 nm in diameter) conjugated to fluorescent reporters and delivered them intravitreally to the adult Balb/C mouse retina. They exhibited persistence in the vitreous and along the inner limiting membrane (ILM) for up to 30 days (longest timepoint examined) but little retinal penetration. We thus evaluated the ability of the small molecule, sulfotyrosine, to disrupt the ILM, and found that 3.2 µg/µL sulfotyrosine led to significant improvement in delivery to the outer retina following intravitreal injections without causing retinal inflammation, degeneration, or loss of function. Co-delivery of sulfotyrosine and HA-NS led to robust improvements in penetration of HA-NS into the retina and accumulation along the interface between the photoreceptors and the retinal pigment epithelium. These exciting findings suggest that sulfotyrosine and HA-NS may be an effective strategy for outer retinal targeting after intravitreal injection.

SUBMITTER: Eblimit A

PROVIDER: S-EPMC8469555 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Peripapillary Intravitreal Injection Improves AAV-Mediated Retinal Transduction.

Project description:The intravitreal (IVT) injection method is a choice when targeting the inner retina for gene therapy. However, the transduction efficiency of adeno-associated virus (AAV) vectors administered by the IVT route is usually low and may be affected by several factors. To improve the transduction efficiency, we developed a novel illuminated long-needle attached injection system and injected AAV2-CMV (cytomegalovirus)-EGFP in front of the retina in rabbit eyes. Ophthalmological examinations were performed and the levels of pro-inflammatory cytokines in the aqueous humor were assessed at the baseline and 1 month, and the results were compared with those of the conventional injection method. Retinal tissues were used for immunohistochemistry. In the ophthalmological examinations, no significant inflammatory signs were detected in both groups, except for transient, mild hyperemia. In the tissues of the rabbits in the peripapillary injection group, significantly increased GFP expression was detected at the ganglion cell and the inner nuclear layers (p < 0.01). There were no differences between groups in glial activation and expressions of interleukin (IL)-6 and IL-8. These results suggest that peripapillary IVT injection in front of the retina would be safe and efficiently transduce viral vectors into the retina of large animals and is considered as a potential method for use in clinical trials.

| S-EPMC7152690 | biostudies-literature

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| S-EPMC7046695 | biostudies-literature

Intravitreal injection associated rhegmatogenous retinal detachment: outcomes of a European analysis.

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| S-EPMC8589788 | biostudies-literature

Treatment patterns of ranibizumab intravitreal injection and dexamethasone intravitreal implant for retinal vein occlusion in the USA.

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| S-EPMC5395996 | biostudies-literature

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| S-EPMC2927518 | biostudies-literature

Intravitreal Injection Technique.

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Intravitreal ziv-aflibercept for macular edema following retinal vein occlusion.

Project description:AIM:To report the efficacy of intravitreal ziv-aflibercept injections in eyes with macular edema due to retinal vein occlusions (RVOs). METHODS:Consecutive patients with persistent or recurrent macular edema (central macula thickness >250 ?m) due to RVO were enrolled in this prospective study. Study eyes received intravitreal injections of ziv-aflibercept (1.25 mg/0.05 mL) at baseline. Patients were reassessed monthly for 4 months and given additional injections pro re nata for worsening best-corrected visual acuity (BCVA), intraretinal edema or subretinal fluid seen on spectral domain optical coherence tomography, or central macular thickness (CMT) measurements >250 ?m. The primary endpoint was improvement in mean CMT at 4 months. Secondary endpoints included improvement in mean BCVA, and ocular and systemic safety signals. RESULTS:Nine eyes (five central and four branch RVOs) of nine patients were enrolled. The mean ± standard deviation CMT decreased from 604±199 ?m at baseline to 319±115 ?m (P=0.001) at 1 month and to 351±205 ?m (P=0.026) at 4 months. The mean BCVA did not improve significantly from baseline (1.00 LogMAR) to the 1-month (0.74 LogMAR; P=0.2) and 4-month (0.71 LogMAR; P=0.13) visits. No safety signals were noted. CONCLUSION:In this small prospective study, intravitreal ziv-aflibercept significantly improved mean CMT in eyes with persistent or recurrent macular edema due to RVOs. Prospective, randomized trials comparing ziv-aflibercept with standard pharmacotherapy are needed to better define efficacy and safety.

| S-EPMC5038569 | biostudies-literature

Systemic pharmacokinetic/pharmacodynamic analysis of intravitreal aflibercept injection in patients with retinal diseases.

Project description:Objective:Explore relationships between systemic exposure to intravitreal aflibercept injection (IAI) and systemic pharmacodynamic effects via post hoc analyses of clinical trials of IAI for neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DME). Methods and analysis:Adults from VGFT-OD-0702.PK (n=6), VGFT-OD-0512 (n= 5), VIEW 2 (n=1204) and VIVID-DME (n=404) studies were included. Validated ELISAs were used to measure concentrations of free and bound aflibercept (reported as adjusted bound) in plasma at predefined time points in each study. Non-compartmental analysis of concentration-time data was obtained with dense sampling in VGFT-OD-0702.PK and VGFT-OD-0512. Sparse sampling was used in VIEW 2 and VIVID-DME. Blood pressure or intrarenal function changes were also investigated. Results:Following intravitreal administration, free aflibercept plasma concentrations quickly decreased once maximum concentrations were achieved at 1-3 days postdose; pharmacologically inactive adjusted bound aflibercept concentrations increased over a longer period and reached plateau 7 days postdose. Ratios of free and adjusted bound aflibercept decreased over time. There were no meaningful changes in systolic/diastolic blood pressure over the duration of each study at all systemic aflibercept exposure levels. For all treatment arms in VIEW 2, there was no clinically relevant change in mean intrarenal function from baseline at week 52. Overall, incidence of systemic adverse events in VIEW 2 and VIVID-DME was low and consistent with the known safety profile of IAI. Conclusion:IAI administration was not associated with systemic effects in patients with nAMD or DME as measured by blood pressure or intrarenal function, two known pharmacologically relevant effects of anti-vascular endothelial growth factor.

| S-EPMC6440611 | biostudies-literature

Efficacy of intravitreal Lucentis injection on major and macular branch retinal vein occlusion.

Project description:BackgroundThe objective of our study was to assess the efficacy of intravitreal Lucentis injection on major and macular branch retinal vein occlusion (BRVO).MethodsIn this retrospective analysis, 43 patients (major BRVO n = 24; macular BRVO, n = 19) were treated with intravitreal injection of Lucentis with a 1 + PRN regimen, which is diagnosed by fluorescein fundus angiography (FFA). "1 + PRN", namely, one intravitreal injection of Lucentis at the baseline, and then continue or stop according to the condition of the patient. The following observation indexes were measured at baseline and follow-up (1-6 months): best corrected visual acuity (BCVA), foveal thickness (CFT), total retinal volume with macular diameter of 6 mm. During the follow-up, repeated injections were given according to patients' demand, and the number of injections was recorded.ResultThe observation indexes of patients with BRVO were significantly improved after 6 months of Lucentis treatment in both major and macular groups, including BCVA, CFT and the retinal volume of the 6 mm-diameter macula. Interestingly, there were significant differences in the therapeutic effect between the two groups, and the macular group had better therapeutic effect than the major group with the less number of repeated injections.ConclusionsTo sum up, intravitreal injection of Lucentis was effective for both major and macular BRVO, and the efficacy in macular subtype group was better than that in major subtype group with the more obviously improvement and the less number of injections.

| S-EPMC7350754 | biostudies-literature

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