In Vivo Delivery Aspects of miRNA, shRNA and siRNA

Khatri, Nirav; Rathi, Mohan; Baradia, Dipesh; Trehan, Sonia; Misra, Ambikanandan

doi:10.1615/critrevtherdrugcarriersyst.v29.i6.20

Cited by 60 publications

(40 citation statements)

References 195 publications

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“…An important advantage of the GEMS ™ technology is that the platform provides the ability to address a wide variety of genes as potential targets for drug discovery, including targets that are known to be medically important but have no assayable function and thus are not tractable by standard screening methodologies. Furthermore, the GEMS ™ technology can be used to identify orally bioavailable compounds that have the potential to be an alternative to RNA therapeutics such as antisense or siRNA that have proven to be difficult to deliver systematically [50;51]. By targeting post-transcriptional regulatory processes unique to diseased tissues in order to modulate the production of proteins of interest, the GEMS ™ approach may have inherent selectivity and safety advantages over other therapeutic modalities.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

et al. 2016

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Current anti-VEGF (Vascular Endothelial Growth Factor A) therapies to treat various cancers indiscriminately block VEGF function in the patient resulting in the global loss of VEGF signaling which has been linked to dose-limiting toxicities as well as treatment failures due to acquired resistance. Accumulating evidence suggests that this resistance is at least partially due to increased production of compensatory tumor angiogenic factors/cytokines. VEGF protein production is differentially controlled depending on whether cells are in the normal “homeostatic” state or in a stressed state, such as hypoxia, by post-transcriptional regulation imparted by elements in the 5’ and 3’ untranslated regions (UTR) of the VEGF mRNA. Using the Gene Expression Modulation by Small molecules (GEMS™) phenotypic assay system, we performed a high throughput screen to identify low molecular weight compounds that target the VEGF mRNA UTR-mediated regulation of stress-induced VEGF production in tumor cells. We identified a number of compounds that potently and selectively reduce endogenous VEGF production under hypoxia in HeLa cells. Medicinal chemistry efforts improved the potency and pharmaceutical properties of one series of compounds resulting in the discovery of PTC-510 which inhibits hypoxia-induced VEGF expression in HeLa cells at low nanomolar concentration. In mouse xenograft studies, oral administration of PTC-510 results in marked reduction of intratumor VEGF production and single agent control of tumor growth without any evident toxicity. Here, we show that selective suppression of stress-induced VEGF production within tumor cells effectively controls tumor growth. Therefore, this approach may minimize the liabilities of current global anti-VEGF therapies.

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Section: Discussionmentioning

confidence: 99%

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

et al. 2016

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“…At the same time, the modifications will need to be biologically compatible, allowing higher translation efficiency. For systemic administration of the modified mRNA, given the experience of siRNA (for review, see Khatri et al 2012;Vader et al 2012: Deng et al 2014), it will be imperative to develop biologically compatible, nontoxic carrier systems to allow delivery to specific organ systems. Because there is no inherent tissue targeting engineered in to the modified mRNA itself (as opposed to ability to use tissue specific promoters in the case of AAV gene therapy vectors [Papadakis et al 2004;Chen et al 2013b;Zacchigna et al 2014]), approaches to destabilize the modified mRNA in nontarget tissues could become of interest.…”

Section: Challenges and Opportunities For Modified Mrna For Cardiovasmentioning

confidence: 99%

Synthetic Chemically Modified mRNA (modRNA): Toward a New Technology Platform for Cardiovascular Biology and Medicine

Chien

Zangi

Lui

2014

Cold Spring Harbor Perspectives in Medicine

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Over the past two decades, a host of new molecular pathways have been uncovered that guide mammalian heart development and disease. The ability to genetically manipulate these pathways in vivo have largely been dependent on the generation of genetically engineered mouse model systems or the transfer of exogenous genes in a variety of DNA vectors ( plasmid, adenoviral, adeno-associated viruses, antisense oligonucleotides, etc.). Recently, a new approach to manipulate the gene program of the adult mammalian heart has been reported that will quickly allow the high-efficiency expression of virtually any protein in the intact heart of mouse, rat, porcine, nonhuman primate, and human heart cells via the generation of chemically modified mRNA (modRNA). The technology platform has important implications for delineating the specific paracrine cues that drive human cardiogenesis, and the pathways that might trigger heart regeneration via the rapid generation of modRNA libraries of paracrine factors for direct in vivo administration. In addition, the strategy can be extended to a variety of other cardiovascular tissues and solid organs across multiple species, and recent improvements in the core technology have supported moving toward the first human studies of modRNA in the next 2 years. These recent advances are reviewed along with projections of the potential impact of the technology for a host of other biomedical problems in the cardiovascular system.

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“…The plasma membrane is a significant barrier for miRNA uptake [179]. Despite their small size, the charge and hydrophilicity of miRNA molecules prevent them from readily crossing the plasma membrane [180].…”

Section: Inefficient Endocytosis and Endosomal Releasementioning

confidence: 99%

MicroRNA and Drug Delivery

Fernandez-Moure

Eps

Weiner

et al. 2014

MicroRNA in Development and in the Progression of Cancer

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The human genome was once thought to be a redundant sequence containing few functional regions coding for proteins. This teaching is being rewritten as we continue to understand the vast complexity of the noncoding regions of the genetic code. These regions we now understand are transcribed into small single-stranded segments or microRNAs (miRNAs) that participate in the regulation of gene expression. miRNAs interact across many pathways and thus have the potential as targets for oncologic therapies. Their efficacy is limited because methods to traverse the many biologic barriers are yet to be developed. In order to achieve effective therapeutic levels at the site of interest, the tumor, the miRNA must be shuttled to the site and simultaneously be protected from the body's defensive mechanisms. To this end, scientists have developed many vehicles for delivery at both the micro-and nanoscale using both synthetic and biologically derived vectors. Viral vectors continue to be the most commonly used vehicles, but are plagued by complications related to the vector itself. These inadequacies led researchers to explore synthetic materials such aspolylactic co-glycolic-acid (PLGA), silicon, gold, and liposomes to overcome the biobarriers of our body. While these vehicles have shown promise, problems such as high clearance rates, poor tumor accumulation and targeting, and adverse reactions have limited their translation into the clinic. In order to overcome these problems, a multistage theory was developed. By decoupling the tasks required of the carrier system, the multistage delivery system is able to simultaneously protect the payload, target the site of interest, and deliver the payload in therapeutic concentrations. This presents a paradigm shift in the concept of drug delivery and may provide the solution to the limited translational gene therapy in oncology.

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In Vivo Delivery Aspects of miRNA, shRNA and siRNA

Cited by 60 publications

References 195 publications

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

Synthetic Chemically Modified mRNA (modRNA): Toward a New Technology Platform for Cardiovascular Biology and Medicine

MicroRNA and Drug Delivery

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