RNAi and Gene Therapy: A Mutual Attraction

Abstract

The phylogenetically conserved cellular phenomenon of RNA interference (RNAi)-the sequence-specific post-transcriptional silencing of gene expression mediated by small double-stranded RNAs-holds substantial promise for basic research and for drug development. Particularly attractive from a medical standpoint is the juxtaposition of new RNAi methodology with established gene transfer strategies, especially viral vectors for efficient and tissue-specific RNAi delivery to patients. Here, we summarize the latest experimental and clinical advances in RNAibased gene therapy approaches. We briefly portray emerging nonviral strategies for siRNA transfer, before comparing the three viral vectors currently predominantly developed as shRNA delivery vehicles, adenovirus, lentivirus, and adeno-associated virus (AAV). Moreover, we describe the most clinically relevant genetic, acquired or infectious targets being pursued for therapeutic purposes. Specifically, we assess the use of vector-mediated RNAi for treatment of viral processes, solid cancers, lymphoproliferative disorders, and neurodegenerative and ocular diseases. In addition, we highlight further emerging applications, including stem cell therapies and animal transgenesis, as well as discuss some of the potential pitfalls and limitations inherent to the individual approaches. While we predict that eventual schemes will be shaped by our increasing understanding of the complexities of human RNAi biology, as well as by progressive refinements of viral shuttle designs, the potential scientific and medical benefits from a successful marriage of RNAi and gene therapy seem enormous.

Binge alcohol drinking is associated with GABAAα2-regulated Toll-like receptor 4 (TLR4) expression in the central amygdala

“…S1). To examine whether these neuroanatomical site-specific elevations are associated with binge drinking, we used the siRNA technology that specifically inhibits one gene at one site (29). The siRNAs and the construction and specificity of the HSV-based vectors (amplicons) used to deliver them are described in SI Materials and Methods (Figs.…”

Radiosensitizing Effect of YM155, a Novel Small-Molecule Survivin Suppressant, in Non–Small Cell Lung Cancer Cell Lines

“…© 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from mitogen-activated protein kinases, and cyclin-dependent kinases, have been shown to suppress survivin expression by targeting various signaling pathways, these drugs inhibit survivin expression nonspecifically (15 -17, 19, 32). Gene therapy strategies based on small interfering RNA or other antisense oligonucleotides are specific for survivin, but the effective delivery of these molecules remains a challenge for the transition to the clinic (33). YM155 is a small-molecule agent that specifically inhibits survivin expression in various types of cancer cell lines in vitro (14).…”

Involvement of Immune Regulation in Multiple Sclerosis

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