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Feature Articles : Jun 15, 2014 ( )
Therapeutic siRNA Interventions
From our June 15 issue: Treatments based on RNA interference are improving now that technologies are delivering longer-lasting gene silencing.!--h2>
The 2006 Nobel Prize in Physiology or Medicine was awarded jointly to Andrew Z. Fire and Craig C. Mello for their 1998 discovery of RNA interference (RNAi), gene silencing by double-stranded RNA.
Today, RNAi-based therapeutics are in Phase II and Phase III clinical trials. The rapid development of this technology demonstrates its enormous potential for treatment of a range of diseases.
The natural capability of certain immune cells, such as dendritic cells, macrophages, and antigen-presenting cells, to recognize nonmethylated CpG motifs in DNA oligonucleotides can be harnessed for cell-specific siRNA delivery, by tricking the cells to internalize siRNAs along with the single-stranded DNA.
HIV Cellular Therapy
Cells that do not express CCR5 are resistant to HIV-1. A recent approach to engineering cellular immunity to HIV infection in normal cells relies on RNAi to functionally knock out most, if not all, of the endogenous expression of CCR5, the primary co-receptor used by HIV-1 to infect a target cell.
Little is known about the processing and trafficking of immunostimulatory types of siRNA. TLR9, the receptor that specifically recognizes nonmethylated DNA, is critical for response to bacteria. It is involved in processing of inflammation due to injuries, and it can lead to very strong systemic immune responses.
Research at the City of Hope showed that macrophages from TLR9-deficient mice internalize CpG-siRNA molecules effectively; however, there is no silencing effect. Molecules tend to stay in the cells, maturing and eventually degrading. In TLR9-positive cells, there is improved trafficking (from endosomes to the endoplasmic reticulum) and release into the cytoplasm. The role of TLR9 in enhancing siRNA release is speculated to be related to TLR9-dependent antigen cross-presentation, which enables transport of the endosomal cargo for processing in the cytoplasm.
Micro-Mediated Control of HCV
Liver-specific microRNA miR-122 plays varied roles in cholesterol metabolism and hepatocellular carcinoma as well as in promoting hepatitis C viral (HCV) replication.
Structural Basis for Gene Silencing
Small-RNA-guided gene regulation has emerged as one of the fundamental principles in cell function. The major protein players in this process are members of the Argonaute protein family, highly specialized binding modules that accommodate the small RNA component and coordinate downstream gene-silencing events.
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