Special delivery: targeted therapy with small RNAs

Peer, Dan; Lieberman, Judy

doi:10.1038/gt.2011.56

Cited by 131 publications

(101 citation statements)

References 65 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several advances have been made in developing methods to deliver siRNA in vivo to different cell types, most successfully to the liver cells (reviewed in refs. [15][16][17]. A lipid-like nanoparticle called C12-200, which had been developed for liverspecific delivery of siRNA, was recently also shown to deliver siRNA to murine monocytes, and silencing C-C chemokine receptor type 2 (CCR2) in monocytes using this reagent was effective in reducing atherosclerosis, islet transplantation and tumors (18).…”

mentioning

confidence: 99%

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Choi

Abraham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsisinduced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ −/− mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ −/− mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ −/− mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.

show abstract

mentioning

confidence: 99%

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Choi

Abraham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The small RNA systems being used in RNAi therapies include siRNA and mimics of endogenous miRNAs. While siRNAs produce the efficient silencing of one specific gene, miRNA mimics tend to suppress the expression of more than one gene, but in a way such that expression is silenced to a lesser degree [13,109]. While canonical mechanisms of RNAi include miRNA, siRNA, and piRNA pathways, CRISPR-Cas can also be viewed as an RNAi system.…”

Section: Overview Of Rnai Therapiesmentioning

confidence: 99%

“…Additionally, RNA sensors in the innate immune system can prohibit effective RNAi by triggering the release of interferons. However, these obstacles are being overcome with the addition of chemical modifications to the RNA which have the ability to disrupt off-target effects without disrupting the silencing of the target gene [109].…”

Section: Obstacles In Therapeutic Rnaimentioning

confidence: 99%

“…Whether or not new delivery systems will be effective depends on the quantitative of siRNA that reaches the cytosol of the target cell and how long it stays actively incorporated into RISC [109].…”

Section: Obstacles In Therapeutic Rnaimentioning

confidence: 99%

“…TD101 targets keratin 6a N171K mutant mRNA, in order to fight pachyonychia congenital (PC1), an autosomal dominant skin disease [109]. Additionally, drugs have been presented with the aim of fighting age-related macular edema, diabetic molecular edema, hepatitis C virus, glaucoma, optic atrophy, amyloidosis, cytomegalovirus, human immunodeficiency virus, human papillomavirus, and many different forms of cancer [13,61,82,109,123]. For example, ALN-VSP02 aims to treat solid liver tumors, EZN-2968 aims to treat lymphoma, advanced solid tumors, and liver metastases, and the FANG vaccine aims to treat ovarian cancer, colon cancer, and other solid tumors.…”

Section: Targets Of Current Researchmentioning

confidence: 99%

See 2 more Smart Citations

Diversity, evolution, and therapeutic applications of small RNAs in prokaryotic and eukaryotic immune systems

Cooper

Overstreet

2014

Physics of Life Reviews

View full text Add to dashboard Cite

Recent evidence supports that prokaryotes exhibit adaptive immunity in the form of CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats) and Cas (CRISPR associated proteins). The CRISPR-Cas system confers resistance to exogenous genetic elements such as phages and plasmids by allowing for the recognition and silencing of these genetic elements. Moreover, CRISPR-Cas serves as a memory of past exposures. This suggests that the evolution of the immune system has counterparts among the prokaryotes, not exclusively among eukaryotes. Mathematical models have been proposed which simulate the evolutionary patterns of CRISPR, however large gaps in our understanding of CRISPR-Cas function and evolution still exist. The CRISPR-Cas system is analogous to small RNAs involved in resistance mechanisms throughout the tree of life, and a deeper understanding of the evolution of small RNA pathways is necessary before the relationship between these convergent systems is to be determined. Presented in this review are novel RNAi therapies based on CRISPR-Cas analogs and the potential for future therapies based on CRISPR-Cas system components.

show abstract

Multifunctional Polymeric Nanosystems for RNA Interference Therapy

Iyer¹,

Ganesh²,

Zhou³

et al. 2013

Pharmaceutical Sciences Encyclopedia

View full text Add to dashboard Cite

RNA interference (RNAi) is one of the most powerful tools for selective silencing of specific aberrant genes for therapeutic management of diseases such as cancer, diabetes, and inflammatory disorders. However, the labile nature of nucleic acid constructs coupled with the difficulty in selectively delivering them to the target tissues, cells, and the intracellular cellular machinery within the cells has been a primary hindrance for the clinical translation of RNAi. Multifunctional nano‐systems provide distinct advantages over other delivery strategies based on their ability to selectively target diseased tissues, such as solid tumors based on passive and active targeting principles. Such nano‐systems can incorporate multiple therapeutic payloads, such as small molecule drugs, small interfering RNAs (siRNAs), and micro RNAs (miRNAs) as well as imaging/contrast agents for simultaneous disease detection, quantifying siRNA/miRNA gene expression/knockdown, examining in vivo fate and sites of localization/excretion, as well as exploring therapeutic potentials in vivo. In this chapter, we have described the principles and mechanisms based on RNA interference phenomenon and the barriers to its successful clinical translation. Furthermore, we have discussed the modes of delivery that have been employed including the advantages of multifunctional polymeric nano‐systems with illustrative examples covering their utility in the management of diseases such as cancer, inflammation, and other chronic diseases.

show abstract

Special delivery: targeted therapy with small RNAs

Cited by 131 publications

References 65 publications

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Diversity, evolution, and therapeutic applications of small RNAs in prokaryotic and eukaryotic immune systems

Multifunctional Polymeric Nanosystems for RNA Interference Therapy

Contact Info

Product

Resources

About