Strategies for ocular siRNA delivery: Potential and limitations of non-viral nanocarriers

Abstract

Controlling gene expression via small interfering RNA (siRNA) has opened the doors to a plethora of therapeutic possibilities, with many currently in the pipelines of drug development for various ocular diseases. Despite the potential of siRNA technologies, barriers to intracellular delivery significantly limit their clinical efficacy. However, recent progress in the field of drug delivery strongly suggests that targeted manipulation of gene expression via siRNA delivered through nanocarriers can have an enormous impact on improving therapeutic outcomes for ophthalmic applications. Particularly, synthetic nanocarriers have demonstrated their suitability as a customizable multifunctional platform for the targeted intracellular delivery of siRNA and other hydrophilic and hydrophobic drugs in ocular applications. We predict that synthetic nanocarriers will simultaneously increase drug bioavailability, while reducing side effects and the need for repeated intraocular injections. This review will discuss the recent advances in ocular siRNA delivery via non-viral nanocarriers and the potential and limitations of various strategies for the development of a ‘universal’ siRNA delivery system for clinical applications.

Cholesterol-Containing Nuclease-Resistant siRNA Accumulates in Tumors in a Carrier-free Mode and Silences MDR1 Gene

“…administration is most often used for therapeutic nucleic acids, local methods for siRNA administration are actively studied in order to achieve a local effect, to prevent systemic toxicity, and to reduce the required dose of the drug 56 . For example, siRNA administered via local routes, such as intravitreal injection, subconjunctival injection, or topical instillation, has been found to be effective in the treatment of ocular diseases 57, 58. One of the most advanced therapeutic siRNA conjugates, equipped with three N -acetylgalactosamine molecules developed by Alnylam for treatment of transthyretin-mediated amyloidosis, is intended for subcutaneous administration 44 .…”

Exosome‐mediated small RNA delivery for gene therapy

“…Optical disease is one of the easiest and safe targets for RNA-based therapy because the eye provides a barrier-free site for local delivery and also mitigates immune response and off-target effects. 32 The only approved therapeutic RNA, Macugen (pegaptanib sodium), is an antivascular endothelial growth factor (anti-VEGF) aptamer that treats wet age-related macular degeneration (AMD). 33 The first clinical trial of small RNA medicine, Bevasiranib, targets VEGF to inhibit retinal neovascularization in patients with AMD and diabetic macular edema.…”

Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines

“…Based on promising preclinical results, several siRNA therapeutics entered clinical trials for ocular disease therapy [8, 20]. Due to the accessibility and the blood ocular barrier, most siRNAs targeting ocular diseases are administered via local routes, such as intravitreal injection, subconjunctival injection, or topical instillation [8, 20].…”

“…Due to the accessibility and the blood ocular barrier, most siRNAs targeting ocular diseases are administered via local routes, such as intravitreal injection, subconjunctival injection, or topical instillation [8, 20]. Therefore, ocular application of siRNA will not be covered in the following PK/BD discussion.…”