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Functional and Anatomic Consequences of Subretinal Dosing in the Cynomolgus Macaque

April 27, 2015

The goal of this study was to characterize functional and anatomic sequelae of a bleb induced by subretinal injection. Subretinal injections (100 µl) of balance salt solution (BSS) were placed in the superotemporal macula of one eye in 3 cynomolgus macaques. Fellow eyes received intravitreal injections (100 µl) of BSS. Fundus photography, ocular coherence tomography (OCT) and multifocal electroretinography (mfERG) were obtained before and immediately after injection and again at intervals up to 3 months post injection. Histopathologic analyses included transmission electron microscopy (TEM) and immunohistochemistry (IHC) for glial fibrillary acidic protein (GFAP), rhodopsin, M/L-cone opsin and S-cone opsin. Results indicated that retinas were re-attached by 2 days post-injection (by OCT). mfERG was suppressed post-subretinal injection within the subretinal injection bleb and surprisingly, also in regions far peripheral to this region. mfERG amplitudes were nearly completely recovered by 90 days. The spectral domain (SD)-OCT inner segment/outer segment (IS/OS) line had decreased reflectivity at 92 days. GFAP and S-cone staining were unaffected. Rhodopsin and M/L-cone opsins were partially displaced into the inner segments. TEM revealed disorganization of the outer segment rod (but not cone) disks. At all post-injection intervals, eyes with intravitreal injection were similar to baseline. In conclusion, subretinal injection is a promising route for drug delivery to the eye. Three months post subretinal injection, retinal function was nearly recovered, although reorganization of the outer segment rod disk remained disrupted. Understanding the functional and anatomic effects of subretinal injection per se is important for interpretation of the effects of compounds delivered to the subretinal space. Subretinal injection is a new potential route for drug delivery to the eye. Separating drug effects from the procedural effects per se is critical.

Nork M, Murphy CJ, Kim CBY, Ver Hoeve JN, Rasmussen CA, Miller PE, Wabers HD, Neider NW, Dubielzig RR, McCulloh RJ, Christian, BJ. Functional and anatomic consequences of subretinal dosing in the cynomolgus macaque. Archives of Ophthalmology, 2012, Jan, 130 (1), 65-75.