Abstract
Ocriplasmin (Jetrea®) is a recombinant protease used to treat vitreomacular traction. To gain insight into vitreoretinal observations reported after ocriplasmin treatment, we have developed an in vivo porcine ocriplasmin-induced posterior vitreous detachment (PVD) model in which we investigated vitreoretinal tissues by optical coherence tomography, histology, and cytokine profiling. Eight weeks postinjection, ocriplasmin yielded PVD in 82% of eyes. Subretinal fluid (85%) and vitreous hyperreflective spots (45%) were resolved by week 3. Histological analysis of extracellular matrix (ECM) proteins such as laminin, fibronectin, and collagen IV indicated no retinal ocriplasmin-induced ECM distribution changes. Retinal morphology was unaffected in all eyes. Cytokine profiles of ocriplasmin-treated eyes were not different from vehicle. In cell-based electrical resistance assays, blood-retinal barrier permeability was altered by ocriplasmin concentrations of 6 μg/mL and higher, with all effects being nontoxic, cell-type specific, and reversible. Ocriplasmin was actively taken up by RPE and Müller cells, and our data suggest both lysosomal and transcellular clearance routes for ocriplasmin. In conclusion, transient hyperreflective spots and fluid in a porcine ocriplasmin-induced PVD model did not correlate with retinal ECM rearrangement nor inflammation. Reversible in vitro effects on blood-retinal barrier permeability provide grounds for a hypothesis on the mechanisms behind transient subretinal fluid observed in ocriplasmin-treated patients.
Highlights
Posterior vitreous detachment (PVD), the release of the vitreous cortex from the internal limiting membrane, is a normal physiologic process related to the aging eye
To gain insight into vitreoretinal observations reported after ocriplasmin treatment, we have developed an in vivo porcine ocriplasmin-induced posterior vitreous detachment (PVD) model in which we investigated vitreoretinal tissues by optical coherence tomography, histology, and cytokine profiling
In order to model ocri plasmin-induced PVD, farm pigs were injected with 96 μg ocriplasmin or vehicle midvitreally and followed up by optical coherence tomography (OCT)
Summary
Posterior vitreous detachment (PVD), the release of the vitreous cortex from the internal limiting membrane, is a normal physiologic process related to the aging eye. One option to treat VMT is vitrectomy surgery, in which the vitreous is removed from the eye and the traction is surgically resolved. Vitrectomy surgery is invasive and has a known risk profile with potential retinal damage and cataract formation [2, 3]. Ocriplasmin is a truncated form of plasmin that is administered via intravitreal injection to induce PVD. It is proposed that the PVD results from enzymatic cleavage of extracellular matrix proteins contributing to the traction, such as fibronectin and laminins at the inner limiting membrane [5,6,7]. Appropriate patient selection, for example, absence of epiretinal membranes, results in a substantially increased efficacy [8, 10,11,12]. The recent OASIS study evaluating the efficacy of ocriplasmin in VMT showed that 41.7% of patients achieved resolution at day 28 versus 6.2% in sham [13]
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