Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?

Abstract

Antisense oligonucleotides can regulate gene expression in living cells. As such, they regulate cell function and division, and can modulate cellular responses to internal and external stresses and stimuli. Although encouraging results from preclinical and clinical studies have been obtained and significant progress has been made in developing these agents as drugs, they are not yet recognized as effective therapeutics. Several major hurdles remain to be overcome, including problems with efficacy, off-target effects, delivery and side effects. The lessons learned from antisense drug development can help in the development of other oligonucleotide-based therapeutics such as CpG oligonucleotides, RNAi and miRNA. KeywordsAntisense; RNAi; Drug targeting; cancer; chemotherapy Historical perspectiveThe development of the antisense approach started in the late 1970s after the discovery that the expression of a specific gene product could be inhibited using a short complementary DNA sequence [1]. Since then, the antisense strategy has enjoyed exponential gains in interest and has been the subject of more than 16,000 publications. Between the appearance of the first publication about the antisense strategy in 1978 and the beginning of intensive antisense research (commencing in the early 1990s) very few studies were published. The increase in antisense research was largely a result of improvements in the methods used for DNA sequencing and synthesizing oligonucleotides [2,3]. Other major milestones in the development of antisense strategies include numerous discoveries about antisense chemistry. The most notable discovery was the addition of a phosphorothioate backbone to the *Correspondence and request for reprints to:

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

“…Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene suppression in skin, a topical delivery route is optimal, given the easy accessibility of skin and the reduced risk of systemic side effects.…”

Endpoint of Cancer Treatment: Targeted Therapies

“…Others have focused on cell signaling molecules implicated in cancer initiation or progression, including the tumor suppressor p53 (mutant), VEGF, IGF-1R, TGF-BII, PKA, and PKCα. Still, other cancer-related molecules have been targeted including survivin, clusterin, ribonucleotide reductase, and DNA methyltransferase (Rayburn and Zhang, 2008).…”

Insights on chiral, backbone modified peptide nucleic acids: Properties and biological activity

“…34 Natural oligonucleotides are not suitable as antisense agents because they are rapidly degraded by exo and endonucleases, present in the serum and in the intracellular environment. 34,35 Modifications able to confer nuclease stability and binding affinity improve AMOs performance. 33 Hence, the same modified oligonucletides used in antisense technology can be used to improve the performance, and the potency, of synthetic agents targeting miRNAs (AMOs or anti-miRNA).…”