/pdf/a-toll-like-receptor-recognizes-bacterial-dna-2lif1icvoq.pdf

A Toll-like receptor recognizes bacterial DNA

Discovered a little over two decades ago, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are noncoding RNAs with important roles in gene regulation. They have recently been investigated as novel classes of therapeutic agents for the treatment of a wide range of disorders including cancers and infections. Clinical trials of siRNA- and miRNA-based drugs have already been initiated. siRNAs and miRNAs share many similarities, both are short duplex RNA molecules that exert gene silencing effects at the post-transcriptional level by targeting messenger RNA (mRNA), yet their mechanisms of action and clinical applications are distinct. The major difference between siRNAs and miRNAs is that the former are highly specific with only one mRNA target, whereas the latter have multiple targets. The therapeutic approaches of siRNAs and miRNAs are therefore very different. Hence, this review provides a comparison between therapeutic siRNAs and miRNAs in terms of their mechanisms of action, physicochemical properties, delivery, and clinical applications. Moreover, the challenges in developing both classes of RNA as therapeutics are also discussed.

/pdf/sirna-versus-mirna-as-therapeutics-for-gene-silencing-qbhofq9n7y.pdf

siRNA Versus miRNA as Therapeutics for Gene Silencing

RNA interference is a naturally occurring endogenous regulatory process where short double-stranded RNA causes sequence-specific posttranscriptional gene silencing. Small interference RNA (siRNA) represents a promising therapeutic strategy. Clinical evaluations of siRNA therapeutics in locoregional treatment settings began in 2004. Systemic siRNA therapy is hampered by the barriers for siRNA to reach their intended targets in the cytoplasm and to exert their gene silencing activity. The three goals of this review were to provide an overview of (a) the barriers to siRNA delivery, from the perspectives of physicochemical properties of siRNA, pharmacokinetics and biodistribution, and intracellular trafficking; (b) the non-viral siRNA carriers including cell-penetrating peptides, polymers, dendrimers, siRNA bioconjugates, and lipid-based siRNA carriers; and (c) the current status of the clinical trials of siRNA therapeutics.

/pdf/delivery-of-sirna-therapeutics-barriers-and-carriers-4vntkrxc8a.pdf

Delivery of siRNA therapeutics: barriers and carriers.

The mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. Seven of these (proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4) and PC7) activate cellular and pathogenic precursor proteins by cleavage at single or paired basic residues, whereas subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) regulate cholesterol and/or lipid homeostasis via cleavage at non-basic residues or through induced degradation of receptors. Proprotein convertases are now considered to be attractive targets for the development of powerful novel therapeutics. In this Review, we summarize the physiological functions and pathological implications of the proprotein convertases, and discuss proposed strategies to control some of their activities, including their therapeutic application and validation in selected disease states.

The biology and therapeutic targeting of the proprotein convertases

A comprehensive overview of exosomes as drug delivery vehicles — Endogenous nanocarriers for targeted cancer therapy

siRNA vs. shRNA: similarities and differences.

Phase I Trial of “bi-shRNAifurin/GMCSF DNA/Autologous Tumor Cell” Vaccine (FANG) in Advanced Cancer

Since its discovery in 1998, RNA interference (RNAi) has revolutionized basic and clinical research. Small RNAs, including small interfering RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA), mediate RNAi effects through either cleavage-dependent or cleavage-independent RNA inducible silencing complex (RISC) effector processes. As a result of its efficacy and potential, RNAi has been elevated to the status of “blockbuster therapeutic” alongside recombinant protein and monoclonal antibody. RNAi has already contributed to our understanding of neoplasia and has great promise for anti-cancer therapeutics, particularly so for personalized cancer therapy. Despite this potential, several hurdles have to be overcome for successful development of RNAi-based pharmaceuticals. This review will discuss the potential for, challenges to, and the current status of RNAi-based cancer therapeutics.

RNA interference and cancer therapy.

Three-year Follow up of GMCSF/bi-shRNA(furin) DNA-transfected Autologous Tumor Immunotherapy (Vigil) in Metastatic Advanced Ewing's Sarcoma.

RNA interference (RNAi) is an evolutionary conserved mechanism for specific gene silencing. This mechanism has great potential for use in targeted cancer therapy. Understanding the RNAi mechanism has led to the development of several novel RNAi-based therapeutic approaches currently in the early phases of clinical trials. It remains difficult to effectively deliver the nucleic acids required in vivo to initiate RNAi, and intense effort is under way in developing effective and targeted systemic delivery systems for RNAi. Description of in vivo delivery systems is not the focus of this review. In this review, we cover the rationale for pursuing personalised cancer therapy with RNAi, briefly review the mechanism of each major RNAi therapeutic technique, summarise and sample recent results with animal models applying RNAi for cancer, and provide an update on current clinical trials with RNAi-based therapeutic agents for cancer therapy. RNAi-based cancer therapy is still in its infancy, and there are numerous obstacles and issues that need to be resolved before its application in personalised therapy focusing on patient-cancer-specific targets can become standard cancer treatment, either alone or in combination with other treatments.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S1462399410001584

Donald Rao

Papers

siRNA vs. shRNA: similarities and differences.

Phase I Trial of “bi-shRNAifurin/GMCSF DNA/Autologous Tumor Cell” Vaccine (FANG) in Advanced Cancer

RNA interference and cancer therapy.

Three-year Follow up of GMCSF/bi-shRNA(furin) DNA-transfected Autologous Tumor Immunotherapy (Vigil) in Metastatic Advanced Ewing's Sarcoma.

Potential use of RNA interference in cancer therapy