Cell-encapsulated device for intraocular delivery of glial-cell derived neurotrophic factor (GDNF)

Abstract

PURPOSE: While GDNF is able to exert neuroprotective effects on photoreceptor cells, successful administration of such therapeutic protein has been hindered by short half-life and the lack of a sustained drug delivery method. A cell-based immunoisolated intraocular drug delivery device for continuous GDNF release was designed. The photoreceptor rescuing effects in a rat model with inherited retinal degeneration were examined after the implantation of the gel device. METHODS: HEK293 cells that overexpress GDNF were encapsulated in a composite matrix constituted of 2mg/ml collagen and 1% alginate. The collagen-alginate gel device was intravitreally injected into Royal College of Surgeons rats on post-natal day 28 (P28). Rats were randomly divided into four groups: sham, un-operated, vehicle control, and treatment groups. Vitreous contents were collected for GDNF content assessment on P35 and P42. Enucleation was carried out on P56 for histological evaluations. H&E stained paraffin sections of the retina were examined for the degree of morphological rescue via quantifying the outer nuclear layer photoreceptors at various retinal regions. RESULTS: Significant amount of GDNF was released into the vitreous after 7 and 14 days of device implantation. Outer nuclear layer (ONL) linings in the treatment group were better aligned at the central retinal regions when compared to the control groups. Increase in mean ONL cell counts were observed across the whole retina, in particularly, the center of the inferior retina. CONCLUSIONS: Cell growth, proliferation and sustained release of GDNF were achieved through implanting the cell-encapsulating collagen-alginate gel device, resulting in morphological rescue of photoreceptor cells in vivo. This system could potentially be applied as a sustained drug release platform of GDNF and/or other therapeutic proteins in various ocular conditions involving similar pathological phenotypes.