Abstract
The use of synthetic RNA for research purposes as well as RNA-based therapy and vaccination has gained increasing importance. Given the anatomical seclusion of the eye, small interfering RNA (siRNA)-induced gene silencing bears great potential for targeted reduction of pathological gene expression that may allow rational treatment of chronic eye diseases in the future. However, there is yet an unmet need for techniques providing safe and efficient siRNA delivery to the retina. We used magnetic nanoparticles (MNPs) and magnetic force (Reverse Magnetofection) to deliver siRNA/MNP complexes into retinal explant tissue, targeting valosin-containing protein (VCP) previously established as a potential therapeutic target for autosomal dominant retinitis pigmentosa (adRP). Safe and efficient delivery of VCP siRNA was achieved into all retinal cell layers of retinal explants from the RHO P23H rat, a rodent model for adRP. No toxicity or microglial activation was observed. VCP silencing led to a significant decrease of retinal degeneration. Reverse Magnetofection thus offers an effective method to deliver siRNA into retinal tissue. Used in combination with retinal organotypic explants, it can provide an efficient and reliable preclinical test platform of RNA-based therapy approaches for ocular diseases.
Highlights
Advances in understanding RNA interference (RNAi)-based signaling pathways have opened up new therapeutic perspectives for a wide range of ocular disorders
We recently generated magnetic nanoparticles (MNPs) for safe and efficient small interfering RNA (siRNA) delivery to cells and tissues assisted by magnetic targeting
Together with the results described above, this shows that all major hallmarks essential for reversal of the autosomal dominant retinitis pigmentosa (adRP) phenotype can be achieved by valosin-containing protein (VCP) silencing through Reverse Magnetofection of the VCP siRNA in this organotypic in vitro model of adRP
Summary
Advances in understanding RNA interference (RNAi)-based signaling pathways have opened up new therapeutic perspectives for a wide range of ocular disorders. A relative immune privilege due to the blood–retina barrier and low lymph drainage minimizes the risk of undesirable side effects [4]. Despite these properties, the delivery of siRNA to the posterior segment of the eye, especially to the retina, has proven to be challenging. Given the low bioavailability of siRNAs due to their high susceptibility to enzymatic hydrolysis, poor cellular uptake and rapid elimination from the circulatory system, as well as potential undesirable side effects due to off-targeting and immunogenicity, siRNA delivery to the retina has encountered many hurdles [5]. Sufficient siRNA bioavailability in this compartment cannot be achieved by either topical [6] or systemic
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