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The Role of RNA Interference in Dermatology: Current Perspectives and Future Directions


November 2012 | Volume 11 | Issue 11 | Feature | 1373 | Copyright © 2012

Abstract

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Introduction

Since its discovery, RNA interference (RNAi) has been studied with great interest for its ability to knock down genes that participate in a variety of disease processes. Translation of RNAi to the clinical arena has been hampered by issues involving stability, targeting and uptake, and immunogenicity.1 Nanomedicine, a rapidly expanding field that utilizes nanoscale materials for the development of therapeutic modalities, has been evaluated as a solution to these impediments as a means to translate RNAi to the bedside.2 A variety of nanomaterial carriers for RNAi therapy are currently being investigated as a means of enhancing stabilization and improving delivery of the enclosed small interfering RNA (siRNA).1 The synergistic effect of encapsulating siRNA in nanoparticle vehicles permits 2 powerful scientific discoveries to be harnessed for more effective therapeutic modalities in order to treat a variety of dermatologic conditions, including malignancy and impaired wound healing.

Mechanism of RNA Interference

RNAi is an innate cellular mechanism of post-transcriptional gene silencing in which small double-stranded RNAs (dsRNA) target specific complementary sequences of messenger RNA (mRNA) for degradation.3-5 RNAi has been evolutionarily conserved in many organisms. By silencing viruses and other genetic elements that synthesize dsRNA intermediates,4 it functions as a mechanism of genome protection. For example, about half the human genome contains transposable elements and repetitive genes, duplicated and inserted in sequences that represent nonfunctional, or "junk," DNA. The silencing of these components by endogenous RNAi pathways is essential to preserving the stability of the genome. This sequence of events begins when long pieces of dsRNA are cleaved into segments called small interfering RNA (siRNA). This is accomplished by ribonuclease III, an enzyme from the Dicer family, yielding fragments composed of 21 to 23 nucleotides.6 These RNA fragments are much shorter than usual mRNAs and ribosomal RNAs. siRNA can be manufactured synthetically and inserted directly into cells. By doing so, the potential for long dsRNA pieces to overwhelm endogenous RNA machinery and disrupt normal protein expression mechanisms is avoided.7 Once siRNA is introduced into the cytoplasm, it is integrated into a protein complex called RNA-induced silencing complex (RISC) (Figure 1).7 A component of the RISC unwinds the siRNA and cleaves the sense strand. The now-activated RISC complex contains the remaining antisense strand of siRNA and selectively targets and degrades the complementary mRNA sequence. The resultant gene silencing persists for 3 to 7 days in rapidly diving cells and for several weeks in nondividing cells.8 The cessation of siRNA's therapeutic effects is due to the dilution of siRNA below a certain threshold as a result of cell division, in addition to degradation within the cell.8

Role of siRNA in Medicine and Dermatology

It was only recently that RNAi became a prominent field of research, when in 1999, Fire et al9 discovered an siRNA that silences gene expression in the nematode Caenorhabditis elegans. In 2001, Elbashir and colleagues10 published a "proof-of-principle" experiment that demonstrated that synthetic siRNA could successfully mediate RNAi by knocking down sequence-specific genes in mammalian cell lines. Soon after these groundbreaking experiments, the first use of siRNA for gene silencing was achieved in a murine model for the therapeutic purpose of targeting a hepatitis C viral sequence.11 The field of RNAi rapidly diversified as gene therapy presented innovative therapeutic approaches, capitalizing on these new mechanisms.12

With the progression of siRNA research, applications in dermatology have emerged in efforts to treat various cutaneous diseases. Skin diseases are particularly amenable to RNAibased therapy, as the therapeutic targets are easily accessible to topical treatments.12,13 Local therapy can be limited to the affected skin, minimizing systemic absorption and toxicity of siRNA as compared with intravenous delivery.13,14 In addition, cutaneous siRNA therapy benefits from the capability to tangibly examine and biopsy the treated region as necessary during treatment. There is a broad spectrum of cutaneous diseases for which gene therapy is an attractive modality, including heritable skin disorders, tumors, metabolic disorders, and infectious diseases.12,15 For example, there is particular interest in applying RNAi in the treatment of heritable skin diseases, where knockdown of a disease-causing gene may demonstrate clinical benefits.13 RNAi has also been researched for treatment of viral skin diseases; for example, siRNA targeting herpes simplex virus proteins has the potential to interfere with active infection.16 However, limitations still exist and must be addressed for RNAi to successfully translate to the bedside.

A major obstacle to utilizing gene silencing via RNAi for therapeutic purposes lies in the delivery of siRNA to specific targets

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