Advances in oligonucleotide drug delivery Roberts, Thomas C; Langer, Robert; Wood, Matthew J A
Nature reviews. Drug discovery,
10/2020, Letnik:
19, Številka:
10
Journal Article
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Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene ...activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.
Food allergy is a common condition for which the only currently approved treatments are avoidance of the allergenic food and administration of emergency medications on accidental exposure. Over the ...past 10 years, significant advances have been made in the field of food immunotherapy, including oral immunotherapy, sublingual immunotherapy, and, more recently, epicutaneous immunotherapy. Each of these approaches are intended to induce some level of desensitization with chronic or repeated exposure to the allergenic food protein, although the risks and potential benefits of each treatment differ significantly. Although new data are emerging at a rapid pace and progress has been substantial, a number of important issues need to be addressed before introduction of these therapies into clinical practice. Furthermore, it is entirely possible that advances in this field will render these current approaches obsolete over the next 20 to 30 years as new and better therapies are developed.
The founding in 1965 of what is now called the Cambridge Structural Database (CSD) has reaped dividends in numerous and diverse areas of chemical research. Each of the million or so crystal ...structures in the database was solved for its own particular reason, but collected together, the structures can be reused to address a multitude of new problems. In this Review, which is focused mainly on the last 10 years, we chronicle the contribution of the CSD to research into molecular geometries, molecular interactions, and molecular assemblies and demonstrate its value in the design of biologically active molecules and the solid forms in which they are delivered. Its potential in other commercially relevant areas is described, including gas storage and delivery, thin films, and (opto)electronics. The CSD also aids the solution of new crystal structures. Because no scientific instrument is without shortcomings, the limitations of CSD research are assessed. We emphasize the importance of maintaining database quality: notwithstanding the arrival of big data and machine learning, it remains perilous to ignore the principle of garbage in, garbage out. Finally, we explain why the CSD must evolve with the world around it to ensure it remains fit for purpose in the years ahead.
The microbiota is vital for the development of the immune system and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the respiratory tract and the gut have recently ...been linked to alterations in immune responses and to disease development in the lungs. In this Opinion article, we review the microbial species that are usually found in healthy gastrointestinal and respiratory tracts, their dysbiosis in disease and interactions with the gut-lung axis. Although the gut-lung axis is only beginning to be understood, emerging evidence indicates that there is potential for manipulation of the gut microbiota in the treatment of lung diseases.
High-throughput sequencing metabarcoding studies in marine biosecurity have largely focused on targeting environmental DNA (eDNA). DNA can persist extracellularly in the environment, making ...discrimination of living organisms difficult. In this study, bilge water samples (i.e., water accumulating on-board a vessel during transit) were collected from 15 small recreational and commercial vessels. eDNA and eRNA molecules were co-extracted and the V4 region of the 18S ribosomal RNA gene targeted for metabarcoding. In total, 62.7% of the Operational Taxonomic Units (OTUs) were identified at least once in the corresponding eDNA and eRNA reads, with 19.5% unique to eDNA and 17.7% to eRNA. There were substantial differences in diversity between molecular compartments; 57% of sequences from eDNA-only OTUs belonged to fungi, likely originating from legacy DNA. In contrast, there was a higher percentage of metazoan (50.2%) and ciliate (31.7%) sequences in the eRNA-only OTUs. Our data suggest that the presence of eRNA-only OTUs could be due to increased cellular activities of some rare taxa that were not identified in the eDNA datasets, unusually high numbers of rRNA transcripts in ciliates, and/or artefacts produced during the reverse transcriptase, PCR and sequencing steps. The proportions of eDNA/eRNA shared and unshared OTUs were highly heterogeneous within individual bilge water samples. Multiple factors including boat type and the activities performed on-board, such as washing of scientific equipment, may play a major role in contributing to this variability. For some marine biosecurity applications analysis, eDNA-only data may be sufficient, however there are an increasing number of instances where distinguishing the living portion of a community is essential. For these circumstances, we suggest only including OTUs that are present in both eDNA and eRNA data. OTUs found only in the eRNA data need to be interpreted with caution until further research provides conclusive evidence for their origin.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Motor learning is a core aspect of human life and appears to be ubiquitous throughout the animal kingdom. Dopamine, a neuromodulator with a multifaceted role in synaptic plasticity, may be a key ...signaling molecule for motor skill learning. Though typically studied in the context of reward-based associative learning, dopamine appears to be necessary for some types of motor learning. Mesencephalic dopamine structures are highly conserved among vertebrates, as are some of their primary targets within the basal ganglia, a subcortical circuit important for motor learning and motor control. With a focus on the benefits of cross-species comparisons, this review examines how "model-free" and "model-based" computational frameworks for understanding dopamine's role in associative learning may be applied to motor learning. The hypotheses that dopamine could drive motor learning either by functioning as a reward prediction error, through passive facilitating of normal basal ganglia activity, or through other mechanisms are examined in light of new studies using humans, rodents, and songbirds. Additionally, new paradigms that could enhance our understanding of dopamine's role in motor learning by bridging the gap between the theoretical literature on motor learning in humans and other species are discussed.
Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs) that function as mediators of intercellular communication by transferring biological information between cells. ...Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and disease.
Resilient, productive soils are necessary to sustainably intensify agriculture to increase yields while minimizing environmental harm. To conserve and regenerate productive soils, the need to ...maintain and build soil organic matter (SOM) has received considerable attention. Although SOM is considered key to soil health, its relationship with yield is contested because of local-scale differences in soils, climate, and farming systems. There is a need to quantify this relationship to set a general framework for how soil management could potentially contribute to the goals of sustainable intensification. We developed a quantitative model exploring how SOM relates to crop yield potential of maize and wheat in light of co-varying factors of management, soil type, and climate. We found that yields of these two crops are on average greater with higher concentrations of SOC (soil organic carbon). However, yield increases level off at ∼2 % SOC. Nevertheless, approximately two-thirds of the world's cultivated maize and wheat lands currently have SOC contents of less than 2 %. Using this regression relationship developed from published empirical data, we then estimated how an increase in SOC concentrations up to regionally specific targets could potentially help reduce reliance on nitrogen (N) fertilizer and help close global yield gaps. Potential N fertilizer reductions associated with increasing SOC amount to 7 % and 5 % of global N fertilizer inputs across maize and wheat fields, respectively. Potential yield increases of 10±11 % (mean ± SD) for maize and 23±37 % for wheat amount to 32 % of the projected yield gap for maize and 60 % of that for wheat. Our analysis provides a global-level prediction for relating SOC to crop yields. Further work employing similar approaches to regional and local data, coupled with experimental work to disentangle causative effects of SOC on yield and vice versa, is needed to provide practical prescriptions to incentivize soil management for sustainable intensification.
To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that ...transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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