The promises and pitfalls of RNA-interference-based therapeutics

Article (PDF Available)inNature 457(7228):426-33 · February 2009with39 Reads
DOI: 10.1038/nature07758 · Source: PubMed
The discovery that gene expression can be controlled by the Watson-Crick base-pairing of small RNAs with messenger RNAs containing complementary sequence - a process known as RNA interference - has markedly advanced our understanding of eukaryotic gene regulation and function. The ability of short RNA sequences to modulate gene expression has provided a powerful tool with which to study gene function and is set to revolutionize the treatment of disease. Remarkably, despite being just one decade from its discovery, the phenomenon is already being used therapeutically in human clinical trials, and biotechnology companies that focus on RNA-interference-based therapeutics are already publicly traded.

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Available from: John J Rossi, Jun 22, 2015
    • "All the recent progresses make gene therapy enter a new revolution. Recent therapeutic trials of siRNA have been carried out with macular degeneration, diabetic macular edema, solid tumors, respiratory diseases, syncytial virus, and human immunodeficiency viral infections, etc. (Novobrantseva et al., 2008; Castanotto and Rossi, 2009; Whitehead et al., 2009). However, Andrew Z. Fire, the Nobel Prize recipient for discovering RNA interference, said that the lack of efficient delivery systems of siRNA may be the next obstacle for gene therapy when he was awarded on the podium in 2006 (Fire, 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Gene delivery systems can be divided to two major types: vector-based (either viral vector or non-viral vector) and physical delivery technologies. Many physical carriers, such as electroporation, gene gun, ultrasound start to be proved to have the potential to enable gene therapy. A relatively new physical delivery technology for gene delivery consists of microneedles (MNs), which has been studied in many fields and for many molecule types and indications. Microneedles can penetrate the stratum corneum, which is the main barrier for drug delivery through the skin with ease of administration and without significant pain. Many different kinds of MNs, such as metal MNs, coated MNs, dissolving MNs have turned out to be promising in gene delivery. In this review, we discussed the potential as well as the challenges of utilizing MNs to deliver nucleic acids for gene therapy. We also proposed that a combination of MNs and other gene delivery approaches may lead to a better delivery system for gene therapy.
    Full-text · Article · May 2016
    • "For example, SPC3649 (a kind of locked nucleic acid) is the first miRNA-targeted drug in clinical trials to inhibit miR-122 expression that is required by hepatitis C virus replication [8] . However, the major hurdles in oligonucleotidesbased therapy are the properties of inefficient delivery and suboptimal pharmacodynamics or pharmacokinetics, which urgently need for small molecule-based intervention strategies [9]. Small molecules maybe suitable agents to regulate miRNA expression, because they are less expensive to produce, easily diffuse across cell membranes, easily delivered into cells as well as having good solubility, bioavailability, and metabolic stability [10]. "
    [Show abstract] [Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression at post-transcriptional level. Increasing evidences show aberrant expression of miRNAs in varieties of diseases. Targeting the dysregulated miRNAs with small molecule drugs has become a novel therapy for many human diseases, especially cancer. Here, we proposed a novel computational approach to identify associations between small molecules and miRNAs based on functional similarity of differentially expressed genes. At the significance level of p < 0.01, we constructed the small molecule and miRNA functional similarity network involving 111 small molecules and 20 miRNAs. Moreover, we also predicted associations between drugs and diseases through integrating our identified small molecule-miRNA associations with experimentally validated disease related miRNAs. As a result, we identified 2265 associations between FDA approved drugs and diseases, in which ~35% associations have been validated by comprehensive literature reviews. For breast cancer, we identified 19 potential drugs, in which 12 drugs were supported by previous studies. In addition, we performed survival analysis for the patients from TCGA and GEO database, which indicated that the associated miRNAs of 4 drugs might be good prognosis markers in breast cancer. Collectively, this study proposed a novel approach to predict small molecule and miRNA associations based on functional similarity, which may pave a new way for miRNA-targeted therapy and drug repositioning.
    Full-text · Article · May 2016
    • "RNA interference (RNAi) has been proven to be a useful approach to treat various genetic diseases. It can down-regulate specific protein expression by silencing the activity of its targeted gene [1] [2] [3] [4] [5]. This approach exhibits significant promises for the development of a new class of molecular therapeutic drugs that interferes with disease-causing or –promoting genes, particularly those that encode the so-called ''non-druggable'' targets not amenable to conventional therapeutics [6] [7]. "
    [Show abstract] [Hide abstract] ABSTRACT: RNA interference (RNAi) mediated gene silencing holds significant promises in gene therapy. A major obstacle to efficient RNAi is the systemic delivery of the therapeutic RNAs into the cytoplasmon whithout being trapped in intracellular endo-/lyso-somes. Herein we report the development of a PEGylated, RGD peptide modified, and disulfide cross-linked short polyethylenimines (DSPEIs)functionalized gold nanorod (RDG) for targeted small hairpin (sh)RNA delivery. The RDG effectively condensed shRNAs into stable nanoparticles, allowing for highly specific targeting of model human brain cancer cells (U-87 MG-GFP)viathe αvβ3integrins-mediated endocytosis. The combined effects of endosomal escape (viathe proton-sponge effect of the PEIs)and efficient cleavage of the disulfide-cross-linked DSPEIsby the high intracellular glutathione content triggered rapid cytoplasma shRNAs release resulted in excellent RNAi efficiency and low cytotoxicity. Furthermore, the high stability and prolonged blood circulation afforded by PEGylation allowed for highly effective, targeted tumor accumulation and internalization of the carriers, resulting in outstanding intra-tumor gene silencing efficiency in U-87 MG-GFP tumor bearing BALB/c mice. Combining the capabilities of both passive and active targeting, intracellular glutathione-triggered "off-on" release and endosomal escape, the RDG nanocarrier developed herein appears to be a highly promising non-viral vector for efficient RNAi. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · May 2015
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