Interfering with disease: a progress report on siRNA-based therapeutics

Abstract

RNA interference (RNAi) quietly crept into biological research in the 1990s when unexpected gene-silencing phenomena in plants and flatworms first perplexed scientists. Following the demonstration of RNAi in mammalian cells in 2001, it was quickly realized that this highly specific mechanism of sequence-specific gene silencing might be harnessed to develop a new class of drugs that interfere with disease-causing or disease-promoting genes. Here we discuss the considerations that go into developing RNAi-based therapeutics starting from in vitro lead design and identification, to in vivo pre-clinical drug delivery and testing. We conclude by reviewing the latest clinical experience with RNAi therapeutics.

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…Whatever the way they are generated, siRNA are recognized by a specific multi-enzyme complex (RISC), that uses the antisense strand as a guide to recognize a specific target mRNA. If the guiding strand and the targeted sequence are fully anti-complementary, cleavage and degradation of the mRNA usually occur while the presence of mismatch at defined positions can lead to inhibition of translation rather than degradation (for extensive reviews see [105][106][107][108]). …”

“…Detailed proteomic analysis is required to identify off-target genes. Off-target and unwanted effects can be minimized by various strategies such as paying attention to nucleotide position in "seed region", including chemical modifications and delivery methods (reviewed by [105]). …”

Efficient in vivo microRNA targeting of liver metastasis

“…MicroRNA-based cancer gene therapy (reviewed by Tong andNemunaitis, 2008 andWeinberg, 2009a) offers the possibility of targeting multiple gene networks controlled by an individual miRNA (Valastyan and Weinberg, 2009b). The efficacy of localized small interfering RNA-based therapeutics (Devi, 2006;de Fougerolles et al, 2007;Davis et al, 2010) against various tumors is currently being assessed in a number of ongoing clinical trials (Tolcher et al, 2002;Chi et al, 2008;Hau et al, 2009). Similarly, miRNAs can be inhibited in vitro with specific cholesterol conjugated (Krutzfeldt et al, 2005), 2 0 -Omethyl oligonucleotide antagonists (AMOs) or 'antagomirs', when delivered as liposomal complexes, or nonconjugated (Esau et al, 2006) into mice, rats and nonhuman primates (Elmen et al, 2008).…”

Atelocollagen-mediated local and systemic applications of myostatin-targeting siRNA increase skeletal muscle mass

“…Since it was demonstrated that siRNAs can intervene gene silencing in mammalian cells without induction of interferon synthesis or nonspecific gene suppression, 2 an increasing number of remedies utilizing highly specific siRNAs targeted against disease-causing or disease-promoting genes have been developed. 3 Effective delivery of active siRNAs to target organs or tissues is therefore the key to the development of RNAi as a broad therapeutic platform. For this purpose, different strategies have been used to deliver and achieve RNAimediated gene silencing in vivo; 3 for example, polymers represent a class of materials that meet the needs of a particular siRNA delivery system, condensing siRNAs into nano-sized particles taken up by cells.…”