Therapeutic short hairpin RNA expression in the liver: viral targets and vectors

Abstract

Over 500 million people worldwide are infected with one or more different and unrelated types of human hepatitis virus. Such individuals are at a high risk of developing acute or chronic hepatic disease, and ultimately dying from sequelae. Although a vaccine is available for hepatitis A and B virus, treatment options for chronically infected patients are limited, and particularly ineffective in case of hepatitis C virus (HCV) infection. A promising new avenue currently being explored is to harness the power of RNA interference for development of an antiviral therapy. The timing to pursue this particular approach is excellent, with the first in vivo animal models for HCV infection becoming available, and the technology for liver-specific expression of short hairpin RNAs advancing at a rapid pace. Here, we critically review these important current developments, and discuss the next steps to bring this novel approach into the clinics.

Proof concept for clinical justification of network mapping for personalized cancer therapeutics

“…65,66 and, furthermore, more amenable to a second layer of tumor specificity via tumor-targeted vector control thereby minimizing nonmalignant cell uptake and potential toxic effect to nontarget agents. [67][68][69][70][71][72] Comparing patient-specific molecular profiles with known pathways and with networks derived from protein interaction databases provides a means for identifying oncotoxic targets. However, the majority of the data underlying our understanding of cancer and, especially, the characterization of cancer gene-protein-metabolic networks, are based on animal and cell line systems.…”

RNAi and Gene Therapy: A Mutual Attraction

“…Notably, this is still sufficient to accommodate at least eight individual shRNA expression cassettes. 25,26 AAV vectors stably and efficiently infect a wide variety of dividing or quiescent cells, and have already been clinically studied in multiple tissues. 1 A unique AAV feature is the option to pseudotype the viral shRNA genome with any of the more than 100 naturally occurring, or with chimeric, synthetically generated capsids.…”

“…A number of recent comprehensive reviews are available. 20,21,25,26 One clinically pertinent viral target for which new treatment options are urgently needed are HBV and HCV. More than 500 million people worldwide are chronic carriers of at least one type of hepatitis virus, and many will ultimately die from infection complications.…”

“…An important example comprises viral hepatitis infections for which the pathogenic agents (e.g., hepatitis A, B, C, or delta virus) are genetically diverse. 25 Once a viral gene transfer vector has been optimized to deliver shRNAs to the commonly infected host cells (in this example, hepatocytes), it can readily be modified to specifically target the genome of any type of hepatitis virus. Second, all viral life cycles include RNA at some point, either in the form of genomic RNA, messenger RNA, or replicative RNA intermediates.…”

Therapeutic application of RNAi: is mRNA targeting finally ready for prime time?

“…Not surprisingly, the outstanding potency, simplicity, and specificity of this evolutionarily conserved gene silencing mechanism has fueled a flurry of efforts to develop novel classes of biotherapeutics based on RNAi. Over the past 5 years, a plethora of in vitro and in vivo proof-of-concept studies have showed that practically every human disease with a gain-of-function genetic lesion can become a target for therapeutic RNAi (5,(7)(8)(9). These studies have been extensively reviewed in detail in the recent literature, and we refer the reader to these articles for specific diseases [cancer, refs.…”