Extracellular vesicles (EVs) are esteemed as a promising delivery vehicle for various genetic therapeutics. They are relatively inert, non-immunogenic, biodegradable, and biocompatible. At least in ...rodents, they can even transit challenging bodily hurdles such as the blood-brain barrier. Constitutively shed by all cells and with the potential to interact specifically with neighboring and distant targets, EVs can be engineered to carry and deliver therapeutic molecules such as proteins and RNAs. EVs are thus emerging as an elegant in vivo gene therapy vector. Deeper understanding of basic EV biology—including cellular production, EV loading, systemic distribution, and cell delivery—is still needed for effective harnessing of these endogenous cellular nanoparticles as next-generation nanodelivery tools. However, even a perfect EV product will be challenging to produce at clinical scale. In this regard, we propose that vector transduction technologies can be used to convert cells either ex vivo or directly in vivo into EV factories for stable, safe modulation of gene expression and function. Here, we extrapolate from the current EV state of the art to a bright potential future using EVs to treat genetic diseases that are refractory to current therapeutics.
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We describe here the use of extracellular vesicles (EVs) as RNA and protein delivery vehicles. We outline the advantages and disadvantage to using EVs as delivery vehicles and posit that EVs will emerge as a bona fide next-generation gene and cell therapy delivery approach.
The rise of regulatory RNA Morris, Kevin V; Mattick, John S
Nature reviews. Genetics,
06/2014, Letnik:
15, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Discoveries over the past decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the ...regulation of genome organization and gene expression, which is increasingly elaborate in complex organisms. Regulatory RNA seems to operate at many levels; in particular, it plays an important part in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here, we review the emergence of the previously unsuspected world of regulatory RNA from a historical perspective.
Recent advances in genomewide studies have revealed the abundance of long non-coding RNAs (lncRNAs) in mammalian transcriptomes. The ENCODE Consortium has elucidated the prevalence of human lncRNA ...genes, which are as numerous as protein-coding genes. Surprisingly, many lncRNAs do not show the same pattern of high interspecies conservation as protein-coding genes. The absence of functional studies and the frequent lack of sequence conservation therefore make functional interpretation of these newly discovered transcripts challenging. Many investigators have suggested the presence and importance of secondary structural elements within lncRNAs, but mammalian lncRNA secondary structure remains poorly understood. It is intriguing to speculate that in this group of genes, RNA secondary structures might be preserved throughout evolution and that this might explain the lack of sequence conservation among many lncRNAs.
Here, we review the extent of interspecies conservation among different lncRNAs, with a focus on a subset of lncRNAs that have been functionally investigated. The function of lncRNAs is widespread and we investigate whether different forms of functionalities may be conserved.
Lack of conservation does not imbue a lack of function. We highlight several examples of lncRNAs where RNA structure appears to be the main functional unit and evolutionary constraint. We survey existing genomewide studies of mammalian lncRNA conservation and summarize their limitations. We further review specific human lncRNAs which lack evolutionary conservation beyond primates but have proven to be both functional and therapeutically relevant.
Pioneering studies highlight a role in lncRNAs for secondary structures, and possibly the presence of functional “modules”, which are interspersed with longer and less conserved stretches of nucleotide sequences. Taken together, high-throughput analysis of conservation and functional composition of the still-mysterious lncRNA genes is only now becoming feasible.
•Recent genomewide studies have revealed the presence of thousands of lncRNAs.•Many lncRNAs do not show the same pattern of conservation as protein-coding genes.•Due to the lack of sequence conservation, functional interpretation is challenging.•The presence, and conservation, of secondary structural elements have been suggested.•This phenomenon remains poorly studied, and we explore what is currently known.
•Infected cells change their transcriptome to express proviral and antiviral lncRNAs.•Many viruses express viral noncoding transcripts essential for viral viability.•Many lncRNAs expressed in the ...infected cell function as positive or negative regulators of the innate antiviral response.
Viral infections induce strong modifications in the cell transcriptome. Among the RNAs whose expression is altered by infection are long noncoding RNAs (lncRNAs). LncRNAs are transcripts with potential to function as RNA molecules. Infected cells may express viral lncRNAs, cellular lncRNAs and chimeric lncRNAs formed by viral and cellular sequences. Some viruses express viral lncRNAs whose function is essential for viral viability. They are transcribed by polymerase II or III and some of them can be processed by unique maturation steps performed by host cell machineries. Some viral lncRNAs control transcription, stability or translation of cellular and viral genes. Surprisingly, similar functions can be exerted by cellular lncRNAs induced by infection. Expression of cellular lncRNAs may be altered in response to viral replication or viral protein expression. However, many cellular lncRNAs respond to the antiviral pathways induced by infection. In fact, many lncRNAs function as positive or negative regulators of the innate antiviral response. Our current knowledge about the identity and function of lncRNAs in infected cells is very limited. However, research into this field has already helped in the identification of novel cellular pathways and may help in the development of therapeutic tools for the treatment of viral infections, autoimmune diseases, neurological disorders and cancer.
The American criminal legal system is an important site of political socialization: scholars have shown that criminal legal contact reduces turnout and that criminalization pushes people away from ...public institutions more broadly. Despite this burgeoning literature, few analyses directly investigate the causal effect of lower-level police contact on voter turnout. To do so, we leverage individual-level administrative ticketing data from Hillsborough County, Florida. We show that traffic stops materially decrease participation for Black and non-Black residents alike, and we also find temporal variation in the effect for Black voters. Although stops reduce turnout more for Black voters in the short term, they are less demobilizing over a longer time horizon. Although even low-level contacts with the police can reduce political participation across the board, our results point to a unique process of political socialization vis-à-vis the carceral state for Black Americans.
Human Immunodeficiency Virus (HIV-1) produces a persistent latent infection. Control of HIV-1 using combination antiretroviral therapy (cART) comes at the cost of life-shortening side effects and ...development of drug-resistant HIV-1. An ideal and safer therapy should be deliverable in vivo and target the stable epigenetic repression of the virus, inducing a stable "block and lock" of virus expression. Towards this goal, we developed an HIV-1 promoter-targeting Zinc Finger Protein (ZFP-362) fused to active domains of DNA methyltransferase 3 A to induce long-term stable epigenetic repression of HIV-1. Cells were engineered to produce exosomes packaged with RNAs encoding this HIV-1 repressor protein. We find here that the repressor loaded anti-HIV-1 exosomes suppress virus expression and that this suppression is mechanistically driven by DNA methylation of HIV-1 in humanized NSG mouse models. The observations presented here pave the way for an exosome-mediated systemic delivery platform of therapeutic cargo to epigenetically repress HIV-1 infection.
Recently, we have witnessed the politicizing effects of police killings in the United States. This project asks how such killings might (de)mobilize voters at the local level. We draw on multiple ...theoretical approaches to develop a theory of community contact with the police. We argue that when a highly visible event tied to government actions occurs—like a police killing—it can spur turnout. This is especially true where public narratives tie such events to government and structural causes. By comparing neighborhoods near a killing before and after election day, we estimate the causal effect on turnout. We find a mobilizing effect. These effects are larger when they “trend” on Google, occur in Black communities, or if the victim is Black. Proximity to a killing also increases support for abolishing the police. We conclude that police violence increases electoral participation in communities where narratives about racially unjust policing resonate most.
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