Terminable cell-encapsulating collagen-alginate composite device for sustained intraocular delivery as a therapy for retinal degenerative diseases

Abstract

Purpose : Retinal degenerative disease (RDD) is a sight-threatening disease with no effective treatment due to the lack of promising drug delivery for rescue of degenerated retinal neurons. Encapsulated cell therapy (ECT) with cellular release of fresh therapeutics enables local sustained drug delivery to the retina while avoiding repeated intravitreal injections. Glial cell-derived neurotrophic factor (GDNF) has shown its neuroprotective effect on photoreceptor cells. While photoreceptor cell death is common in most RDD, we hypothesized that continuous GDNF delivery by collagen-alginate composite (CAC) ECT device can rescue photoreceptor cells, finally slowing the RDD progression. Here, an injectable CAC ECT device equipped with a Tet-on Caspase 8 system was developed for sustained intraocular delivery of GDNF in rabbit eyes.

Methods : Intravitreal (IV) injection of CAC ECT device was performed on healthy New Zealand White rabbits. Three or six units of CAC ECT device were injected into the rabbit eye and kept for 2 weeks, after which rabbits were sacrificed, and devices were retrieved. CAC ECT device biostability was determined by evaluation of gel morphology, cell viability and internal structure. Its biosafety was examined by assessment of flash electroretinogram (fERG), intraocular pressure (IOP) and retinal histology. Rabbits receiving 3 ECT devices were also given 0.1mg/ml doxycycline in drinking water 7 days post-operation for 1 week to examine gel termination efficacy. Cell viability in retrieved devices was determined by MTS assay and Live-Dead assay.

Results : Our data showed that IV injection of CAC ECT device was safe and imposed no changes on retinal function and morphology. The retrieved CAC ECT device exhibited good mechanical stability, gel integrity with no material degradation, and no host tissue attachment with viable encapsulated cells. Scanning electron microscopy further revealed CAC interpenetrating network and colonies of living cells. A week of oral doxycycline treatment could effectively stop the CAC ECT device.

Conclusions : Our CAC ECT device was safe and terminable after IV injection. It demonstrated good mechanical stability while entrapped cells maintained their viability, suggesting that it is a promising drug delivery platform to treat RDD.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.