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Special Issue "RNAi-Based Therapeutics"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 December 2012)

Special Issue Editor

Guest Editor
Prof. Dr. John J. Rossi

Department of Molecular and Cellular Biology, Irell and Manella Graduate School of Biological Sciences, Beckman Research Int. of City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
E-Mail
Phone: 626 301 8360
Interests: siRNA; shRNA; RNAi; aptamers; small RNA gene activators; silencers

Published Papers (12 papers)

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Displaying articles 1-12
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Research

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Open AccessArticle Methods for Evaluating Cell-Specific, Cell-Internalizing RNA Aptamers
Pharmaceuticals 2013, 6(3), 295-319; doi:10.3390/ph6030295
Received: 11 January 2013 / Revised: 9 February 2013 / Accepted: 1 March 2013 / Published: 14 March 2013
Cited by 14 | PDF Full-text (1085 KB) | HTML Full-text | XML Full-text
Abstract
Recent clinical trials of small interfering RNAs (siRNAs) highlight the need for robust delivery technologies that will facilitate the successful application of these therapeutics to humans. Arguably, cell targeting by conjugation to cell-specific ligands provides a viable solution to this problem. Synthetic RNA
[...] Read more.
Recent clinical trials of small interfering RNAs (siRNAs) highlight the need for robust delivery technologies that will facilitate the successful application of these therapeutics to humans. Arguably, cell targeting by conjugation to cell-specific ligands provides a viable solution to this problem. Synthetic RNA ligands (aptamers) represent an emerging class of pharmaceuticals with great potential for targeted therapeutic applications. For targeted delivery of siRNAs with aptamers, the aptamer-siRNA conjugate must be taken up by cells and reach the cytoplasm. To this end, we have developed cell-based selection approaches to isolate aptamers that internalize upon binding to their cognate receptor on the cell surface. Here we describe methods to monitor for cellular uptake of aptamers. These include: (1) antibody amplification microscopy, (2) microplate-based fluorescence assay, (3) a quantitative and ultrasensitive internalization method (“QUSIM”) and (4) a way to monitor for cytoplasmic delivery using the ribosome inactivating protein-based (RNA-RIP) assay. Collectively, these methods provide a toolset that can expedite the development of aptamer ligands to target and deliver therapeutic siRNAs in vivo. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessArticle Targeted CRM197-PEG-PEI/siRNA Complexes for Therapeutic RNAi in Glioblastoma
Pharmaceuticals 2011, 4(12), 1591-1606; doi:10.3390/ph4121591
Received: 16 September 2011 / Revised: 8 December 2011 / Accepted: 9 December 2011 / Published: 16 December 2011
Cited by 5 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
RNA interference (RNAi) allows the specific knockdown of tumor relevant genes. To induce RNAi, the delivery of small interfering RNAs (siRNAs) is of crucial importance. This is particularly challenging for their therapeutic applications in vivo. Low molecular weight branched polyethylenimine (PEI) is
[...] Read more.
RNA interference (RNAi) allows the specific knockdown of tumor relevant genes. To induce RNAi, the delivery of small interfering RNAs (siRNAs) is of crucial importance. This is particularly challenging for their therapeutic applications in vivo. Low molecular weight branched polyethylenimine (PEI) is safe and efficient for nucleic acid delivery including small RNA molecules, based on its ability to electrostatically complex siRNA molecules, thereby protecting them from nuclease degradation. The nanoscale PEI/siRNA complexes are endocytosed by cells prior to intracellular complex release from the lysosome and cytoplasmic release of the siRNAs from the complexes. Chemical modification and ligand decoration of the complexes aim at introducing target tissue specificity and further increased efficacy of PEI-mediated siRNA delivery. CRM197 is a mutated, non-toxic diphtheria toxin (DT) that binds to the membrane-bound precursor of HB-EGF-like growth factor/diphtheria toxin receptor highly expressed in glioblastoma cells. Likewise, the growth factor pleiotrophin (PTN/HB-GAM/HARP) is overexpressed in glioblastoma and is rate limiting for tumor growth, thus representing an attractive target gene for therapeutic knockdown approaches. PEGylation of PEI was performed to reduce the surface charge, and by CRM197 coupling we prepared a modified PEI for siRNA delivery into glioblastoma cells. The novel PEI conjugates were analyzed for their complexation efficiency and optimal mixing ratios, and complexes were physicochemically characterized regarding stability, size and zeta potential. The biological activity of the complexes was confirmed in cell culture by reporter gene knockdown. For the therapeutic treatment of subcutaneous human gliobastoma xenografts in athymic nude mice, we systemically injected the modified PEI/siRNA complexes targeting PTN. Antitumor effects based on PTN knockdown demonstrated the advantage of tumor-targeted CRM197-PEG-PEI/siRNA over untargeted PEG-PEI polyplexes. Thus, we establish targeted CRM197-PEG-PEI-based complexes for siRNA delivery in vivo, and show therapeutic effects of CRM197-PEG-PEI/siRNA-mediated knockdown of PTN. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)

Review

Jump to: Research

Open AccessReview New Aspects of Gene-Silencing for the Treatment of Cardiovascular Diseases
Pharmaceuticals 2013, 6(7), 881-914; doi:10.3390/ph6070881
Received: 29 March 2013 / Revised: 15 June 2013 / Accepted: 11 July 2013 / Published: 19 July 2013
Cited by 1 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text
Abstract
Coronary heart disease (CHD), mainly caused by atherosclerosis, represents the single leading cause of death in industrialized countries. Besides the classical interventional therapies new applications for treatment of vascular wall pathologies are appearing on the horizon. RNA interference (RNAi) represents a novel therapeutic
[...] Read more.
Coronary heart disease (CHD), mainly caused by atherosclerosis, represents the single leading cause of death in industrialized countries. Besides the classical interventional therapies new applications for treatment of vascular wall pathologies are appearing on the horizon. RNA interference (RNAi) represents a novel therapeutic strategy due to sequence-specific gene-silencing through the use of small interfering RNA (siRNA). The modulation of gene expression by short RNAs provides a powerful tool to theoretically silence any disease-related or disease-promoting gene of interest. In this review we outline the RNAi mechanisms, the currently used delivery systems and their possible applications to the cardiovascular system. Especially, the optimization of the targeting and transfection procedures could enhance the efficiency of siRNA delivery drastically and might open the way to clinical applicability. The new findings of the last years may show the techniques to new innovative therapies and could probably play an important role in treating CHD in the future. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver
Pharmaceuticals 2013, 6(5), 659-680; doi:10.3390/ph6050659
Received: 28 March 2013 / Revised: 10 April 2013 / Accepted: 24 April 2013 / Published: 29 April 2013
Cited by 42 | PDF Full-text (693 KB) | HTML Full-text | XML Full-text
Abstract
Many aspects of intercellular communication are mediated through “sending” and “receiving” packets of information via the secretion and subsequent receptor-mediated detection of biomolecular species including cytokines, chemokines, and even metabolites. Recent evidence has now established a new modality of intercellular communication through which
[...] Read more.
Many aspects of intercellular communication are mediated through “sending” and “receiving” packets of information via the secretion and subsequent receptor-mediated detection of biomolecular species including cytokines, chemokines, and even metabolites. Recent evidence has now established a new modality of intercellular communication through which biomolecular species are exchanged between cells via extracellular lipid vesicles. A particularly important class of extracellular vesicles is exosomes, which is a term generally applied to biological nanovesicles ~30–200 nm in diameter. Exosomes form through invagination of endosomes to encapsulate cytoplasmic contents, and upon fusion of these multivesicular endosomes to the cell surface, exosomes are released to the extracellular space and transport mRNA, microRNA (miRNA) and proteins between cells. Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo. It is possible that such functional delivery of biomolecules indicates that exosomes utilize native mechanisms (e.g., for internalization and trafficking) that may be harnessed by using exosomes to deliver exogenous RNA for therapeutic applications. A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for “reverse engineering” such mechanisms to improve the performance of synthetic delivery vehicles. In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
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Open AccessReview Disease-Causing Allele-Specific Silencing by RNA Interference
Pharmaceuticals 2013, 6(4), 522-535; doi:10.3390/ph6040522
Received: 27 December 2012 / Revised: 28 March 2013 / Accepted: 2 April 2013 / Published: 11 April 2013
Cited by 6 | PDF Full-text (270 KB) | HTML Full-text | XML Full-text
Abstract
Small double-stranded RNAs (dsRNAs) of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA) duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi). Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become
[...] Read more.
Small double-stranded RNAs (dsRNAs) of approximately 21-nucleotides in size, referred to as small interfering RNA (siRNA) duplexes, can induce sequence-specific posttranscriptional gene silencing, or RNA interference (RNAi). Since chemically synthesized siRNA duplexes were found to induce RNAi in mammalian cells, RNAi has become a powerful reverse genetic tool for suppressing the expression of a gene of interest in mammals, including human, and its application has been expanding to various fields. Recent studies further suggest that synthetic siRNA duplexes have the potential for specifically inhibiting the expression of an allele of interest without suppressing the expression of other alleles, i.e., siRNA duplexes likely confer allele-specific silencing. Such gene silencing by RNAi is an advanced technique with very promising applications. In this review, I would like to discuss the potential utility of allele-specific silencing by RNAi as a therapeutic method for dominantly inherited diseases, and describe possible improvements in siRNA duplexes for enhancing their efficacy. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview Delivery of RNAi-Based Oligonucleotides by Electropermeabilization
Pharmaceuticals 2013, 6(4), 510-521; doi:10.3390/ph6040510
Received: 31 December 2012 / Revised: 19 March 2013 / Accepted: 27 March 2013 / Published: 10 April 2013
PDF Full-text (622 KB) | HTML Full-text | XML Full-text
Abstract
For more than a decade, understanding of RNA interference (RNAi) has been a growing field of interest. The potent gene silencing ability that small oligonucleotides have offers new perspectives for cancer therapeutics. One of the present limits is that many biological barriers exist
[...] Read more.
For more than a decade, understanding of RNA interference (RNAi) has been a growing field of interest. The potent gene silencing ability that small oligonucleotides have offers new perspectives for cancer therapeutics. One of the present limits is that many biological barriers exist for their efficient delivery into target cells or tissues. Electropermeabilization (EP) is one of the physical methods successfully used to transfer small oligonucleotides into cells or tissues. EP consists in the direct application of calibrated electric pulses to cells or tissues that transiently permeabilize the plasma membranes, allowing efficient in vitro and in vivo. cytoplasmic delivery of exogenous molecules. The present review reports on the type of therapeutic RNAi-based oligonucleotides that can be electrotransferred, the mechanism(s) of their electrotransfer and the technical settings for pre-clinical purposes. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview Design of siRNA Therapeutics from the Molecular Scale
Pharmaceuticals 2013, 6(4), 440-468; doi:10.3390/ph6040440
Received: 24 January 2013 / Revised: 27 February 2013 / Accepted: 13 March 2013 / Published: 25 March 2013
Cited by 11 | PDF Full-text (679 KB) | HTML Full-text | XML Full-text
Abstract
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the
[...] Read more.
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview RNAi Therapeutics in Autoimmune Disease
Pharmaceuticals 2013, 6(3), 287-294; doi:10.3390/ph6030287
Received: 31 December 2012 / Revised: 18 February 2013 / Accepted: 27 February 2013 / Published: 5 March 2013
Cited by 4 | PDF Full-text (127 KB) | HTML Full-text | XML Full-text
Abstract
Since the discovery of RNA interference (RNAi), excitement has grown over its potential therapeutic uses. Targeting RNAi pathways provides a powerful tool to change biological processes post-transcriptionally in various health conditions such as cancer or autoimmune diseases. Optimum design of shRNA, siRNA, and
[...] Read more.
Since the discovery of RNA interference (RNAi), excitement has grown over its potential therapeutic uses. Targeting RNAi pathways provides a powerful tool to change biological processes post-transcriptionally in various health conditions such as cancer or autoimmune diseases. Optimum design of shRNA, siRNA, and miRNA enhances stability and specificity of RNAi-based approaches whereas it has to reduce or prevent undesirable immune responses or off-target effects. Recent advances in understanding pathogenesis of autoimmune diseases have allowed application of these tools in vitro as well as in vivo with some degree of success. Further research on the design and delivery of effectors of RNAi pathway and underlying molecular basis of RNAi would warrant practical use of RNAi-based therapeutics in human applications. This review will focus on the approaches used for current therapeutics and their applications in autoimmune diseases, including rheumatoid arthritis and Sjögren’s syndrome. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview RNAi Therapeutic Platforms for Lung Diseases
Pharmaceuticals 2013, 6(2), 223-250; doi:10.3390/ph6020223
Received: 19 December 2012 / Revised: 19 January 2013 / Accepted: 1 February 2013 / Published: 6 February 2013
Cited by 26 | PDF Full-text (1276 KB) | HTML Full-text | XML Full-text
Abstract
RNA interference (RNAi) is rapidly becoming an important method for analyzing gene functions in many eukaryotes and holds promise for the development of therapeutic gene silencing. The induction of RNAi relies on small silencing RNAs, which affect specific messenger RNA (mRNA) degradation. Two
[...] Read more.
RNA interference (RNAi) is rapidly becoming an important method for analyzing gene functions in many eukaryotes and holds promise for the development of therapeutic gene silencing. The induction of RNAi relies on small silencing RNAs, which affect specific messenger RNA (mRNA) degradation. Two types of small RNA molecules, i.e. small interfering RNAs (siRNAs) and microRNAs (miRNAs), are central to RNAi. Drug discovery studies and novel treatments of siRNAs are currently targeting a wide range of diseases, including various viral infections and cancers. Lung diseases in general are attractive targets for siRNA therapeutics because of their lethality and prevalence. In addition, the lung is anatomically accessible to therapeutic agents via the intrapulmonary route. Recently, increasing evidence indicates that miRNAs play an important role in lung abnormalities, such as inflammation and oncogenesis. Therefore, miRNAs are being targeted for therapeutic purposes. In this review, we present strategies for RNAi delivery and discuss the current state-of-the-art RNAi-based therapeutics for various lung diseases. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview siRNA Genome Screening Approaches to Therapeutic Drug Repositioning
Pharmaceuticals 2013, 6(2), 124-160; doi:10.3390/ph6020124
Received: 20 December 2012 / Revised: 10 January 2013 / Accepted: 22 January 2013 / Published: 28 January 2013
Cited by 6 | PDF Full-text (594 KB) | HTML Full-text | XML Full-text
Abstract
Bridging high-throughput screening (HTS) with RNA interference (RNAi) has allowed for rapid discovery of the molecular basis of many diseases, and identification of potential pathways for developing safe and effective treatments. These features have identified new host gene targets for existing drugs paving
[...] Read more.
Bridging high-throughput screening (HTS) with RNA interference (RNAi) has allowed for rapid discovery of the molecular basis of many diseases, and identification of potential pathways for developing safe and effective treatments. These features have identified new host gene targets for existing drugs paving the pathway for therapeutic drug repositioning. Using RNAi to discover and help validate new drug targets has also provided a means to filter and prioritize promising therapeutics. This review summarizes these approaches across a spectrum of methods and targets in the host response to pathogens. Particular attention is given to the utility of drug repurposing utilizing the promiscuous nature of some drugs that affect multiple molecules or pathways, and how these biological pathways can be targeted to regulate disease outcome. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges
Pharmaceuticals 2013, 6(1), 85-107; doi:10.3390/ph6010085
Received: 21 December 2012 / Revised: 8 January 2013 / Accepted: 14 January 2013 / Published: 16 January 2013
Cited by 77 | PDF Full-text (222 KB) | HTML Full-text | XML Full-text
Abstract
RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery
[...] Read more.
RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi therapeutics are highlighted. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Open AccessReview Potential Use of Polyamidoamine Dendrimer Conjugates with Cyclodextrins as Novel Carriers for siRNA
Pharmaceuticals 2012, 5(1), 61-78; doi:10.3390/ph5010061
Received: 31 October 2011 / Revised: 20 December 2011 / Accepted: 21 December 2011 / Published: 30 December 2011
Cited by 11 | PDF Full-text (572 KB) | HTML Full-text | XML Full-text
Abstract
Cyclodextrin (CyD)-based nanoparticles and polyamidoamine (PAMAM) starburst dendrimers (dendrimers) are used as novel carriers for DNA and RNA. Recently, small interfering RNA (siRNA) complex with β-CyD-containing polycations (CDP) having adamantine-PEG or adamantine-PEG-transferrin underwent a phase I study for treatment of solid tumors. Multifunctional
[...] Read more.
Cyclodextrin (CyD)-based nanoparticles and polyamidoamine (PAMAM) starburst dendrimers (dendrimers) are used as novel carriers for DNA and RNA. Recently, small interfering RNA (siRNA) complex with β-CyD-containing polycations (CDP) having adamantine-PEG or adamantine-PEG-transferrin underwent a phase I study for treatment of solid tumors. Multifunctional dendrimers can be used for a wide range of biomedical applications, including the interaction and intracellular delivery of DNA and RNA. The present review will address the latest developments in dendrimer conjugates with cyclodextrins for siRNA delivery including the novel sustained release system. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
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