Small‐interfering RNAs (siRNAs) as a promising tool for ocular therapy

Abstract

RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments. AbbreviationsAMD, age-related macular degeneration; Apaf-1, apoptotic protease-activating factor-1; CNV, choroidal neovascularization; CTGF, connective tissue growth factor; DR, diabetic retinopathy; dsRNA, double-stranded RNA; ECM, extracellular matrix; HIF-1α, hypoxia-inducible factor-1α; IOP, intraocular pressure; ONC, optic nerve crush; POAG, open-angle glaucoma; RGC, retinal ganglion cell; RISC, RNA-induced silencing complex; RNAi, RNA interference; RP, retinitis pigmentosa; Smad, signalling mathers against decapentaplegic; SPARC, secreted protein acidic and rich in cysteine; TLR3, toll-like receptor 3; TM, trabecular meshwork; TXNIP, thioredoxin interacting protein IntroductionRNA interference (RNAi) technology has been used to elucidate gene function, to generate model systems and to identify new molecular targets. In addition, RNAi is currently progressing from basic research to potential therapeutic applications. Because any gene that causes or contributes to a disease is susceptible to suppression by RNAi, RNAi therapy represents a promising biomedical strategy for treating a diverse range of diseases including cancer, cardiovascular diseases, neurodegenerative diseases, inflammatory conditions, viral infections and ocular diseases (Guo et al., 2010). In particular, the accessibility of the eye facilitates small-interfering RNA (siRNA) delivery, and naked siRNA has been efficiently applied by topical administration to the anterior segment or by intravitreal injection to the posterior segment (de Fougerolles, 2008). As the localized delivery of siRNA to the eye is less challenging than for other tissues, there has been significant progress made towards its use as a therapeutic procedure for eye diseases. In fact, several siRNA-based therapeutic agents for o...

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms

“…78 Clinical trials of intravitreal siRNA treatments, including those targeting RTP801, have reported safety and efficacy for ocular diseases. 48,50,86 Despite the inherent vulnerabilities of immunofluorescence-based analyses, such as antibody specificity and limitations of sampling for neuronal/glial quantification, both our in vivo and in vitro observations yielded consistent results. Here, we show that siRNA-mediated knockdown of RTP801 promotes RGC neuroprotection, supports elongation of regenerating axons after ONC in vivo, and potentiates a proregenerative reactive glial response to injury.…”

An Overview of Various Carriers for siRNA Delivery

“…Although the use of siRNA therapy for diseases in the eyes have many advantages, this type of treatment can be further enhanced with more advancements in the development of controlled/targeted delivery techniques for siRNA to the eyes. [77] siRNAs can even potentially be used for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease. [78] …”

Corneal Neovascularization and Treatment: Review

“…Endotelyal tip hücreler, HIFs, talidomid, anjiyostatin, endostatin, fumagillin, COX-2 inhibitörleri, Fc endotelin enjeksiyonu, si-RNA bu nedenle araştı-rılan moleküllerden bazıları olup, gen tedavisinde geliştirilmektedir. [75][76][77] Günümüzde anjiyogenezde rol alan faktörle-rin sentezine gen tedavisi ile müdahale mümkün hâle gelmiştir. Gen transferi için replikasyon özel-liği olmayan viral ve nonviral taşıyıcılar kullanıl-maktadır.…”