Neuroprotective Effect of siRNA Entrapped in Hyaluronic Acid-Coated Lipoplexes by Intravitreal Administration

Abstract

Since the possibility of silencing specific genes linked to retinal degeneration has become a reality with the use of small interfering RNAs (siRNAs), this technology has been widely studied to promote the treatment of several ocular diseases. Despite recent advances, the clinical success of gene silencing in the retina is significantly reduced by inherent anatomical and physiological ocular barriers, and new strategies are required to achieve intraocular therapeutic effectiveness. In this study, we developed lipoplexes, prepared with sodium alginate as an adjuvant and strategically coated with hyaluronic acid (HA-LIP), and investigated the potential neuroprotective effect of these systems in a retinal light damage model. Successful functionalization of the lipoplexes with hyaluronic acid was indicated in the dynamic light scattering and transmission electron microscopy results. Moreover, these HA-LIP nanoparticles were able to protect and deliver siRNA molecules targeting caspase-3 into the retina. After retinal degeneration induced by high light exposure, in vitro and in vivo quantitative reverse transcription-PCR (RT-qPCR) assays demonstrated significant inhibition of caspase-3 expression by HA-LIP. Furthermore, these systems were shown to be safe, as no evidence of retinal toxicity was observed by electroretinography, clinical evaluation or histology.

Application Prospects for Synthetic Nanoparticles in Optogenetic Retinal Prosthetics

“…In another study [118] on an ex vivo model (isolated bovine eyes, human pigment epithelium cell culture), it was shown that the coating of plasmid DNA lipoplexes with hyaluronic acid results in a noticeable increase in the internalization and transfection efficiency, and also increases the mobility of such lipoplexes in the vitreous matrix. Quite promising results have also been obtained in one of the recent studies [119], where hyaluronic acid-coated lipoplexes after intravitreal injection to rats delivered miRNA against caspase-3 (activated in retinal degeneration) into various retinal cells, exerting thereby a neuroprotective effect. Besides, in this work, potential retinotoxicity of such particles was separately evaluated retinographically, and it was shown that they have no toxic effects.…”

Next-Generation Nanomedicine Approaches for the Management of Retinal Diseases

“…Successful gene transfer using liposomal eye drops has also been reported in the retina, though it has not been evaluated in retinal disease models [ 73 ]. In a previous study, intravitreal injection of a siRNA-entrapped hyaluronic acid-coated lipoplex demonstrated significant neuroprotective effects in a retinal light damage model, without evidence of retinal toxicity [ 137 ]. Systemic administration of a rosiglitazone-loaded liposomal formulation resulted in neuroprotection in the retina of a rotenone-insult Parkinson’s disease rodent model [ 138 ].…”

Strategies to Improve the Targeting of Retinal Cells by Non-Viral Gene Therapy Vectors

“…Hyaluronic acid can also be used to coat other non-viral vectors such as lipoplexes (HA-LIP), as demonstrated by an in vitro and in vivo study on a retina light damage model. HA-LIP carrying siRNA targeting caspase-3 were able to inhibit the apoptosis cascade thus preventing retinal degeneration (Ribeiro et al, 2021).…”