Non‐invasive, needle‐free drug delivery for treatment of retinal degeneration on Bardet‐Biedl syndrome

Purpose To develop a non‐invasive drug delivery system based on superparamagnetic nanoparticles (NP) for the treatment of retinal degeneration on Bardet‐Biedl syndrome (BBS). The delivery system will be used to deliver two small molecules, valproic acid (VPA) and Guanabenz (GBZ). Methods A mixture of two NP (one loaded with VPA and other with GBZ) was applied as eyedrops on 14‐days old mice with the use of a magnetic field. The treatment was assessed in both wild type and a mice model for BBS (Bbs12−/−). The effects of the treatment were evaluated 2 weeks post treatment at 1‐month‐old. Retinal structure and function were analysed using electroretinogram recordings (ERG), histology and transmission electron microscopy (TEM). Results In vitro studies showed no important toxic effects in cell cultures for retinal pigmented epithelium (RPE1) and 661W (murine photoreceptor precursor) after treatment with unloaded NP. Scotopic and photopic ERG recordings showed no toxic effect of the NP on photoreceptor (PR) function. TEM analysis indicated the presence of the NP in the PR layer of the retina after eyedrop application. TEM images showed a decrease in Endoplasmic Reticulum (ER) dilatation. The treated group with loaded NP showed an increase in the thickness of the inner nuclear layer, outer nuclear layer, inner PR segment and outer PR segment. Conclusions These results highlight the potential for these NP for non‐invasive drug delivery to the retina. Both the presence of the NP and biological effect were shown in our mouse model. The VPA and GBZ combination has already shown decrease of cell death mediated by ER stress in the Bbs12−/− model. This is an unmet clinical need with no curative treatment for retinal ciliopathies. The possibility of delaying PR death would increase the therapeutic window of gene therapy potentially increasing its effectivity.