Studies on siRNA delivery have seen intense growth in the past decades since siRNA has emerged as a new class of gene therapeutics for the treatment of various diseases. siRNA bioconjugate, as one of ...the major delivery strategies, offers the potential to enhance and broaden pharmacological properties of siRNA, while minimizing the heterogeneity and stability-correlated toxicology. This review summarizes the recent developments of siRNA bioconjugate, including the conjugation with antibody, peptide, aptamer, small chemical, lipidoid, cell-penetrating peptide polymer, and nanoparticle. These siRNA bioconjugate, either administrated alone or formulated with other agents, could significantly improve pharmacokinetic behavior, enhance the biological half-life, and increase the targetability while maintaining sufficient gene silencing activity, with a concomitant improvement of the therapeutic outcomes and diminishment of adverse effects. This review emphasizes the delivery application of these siRNA bioconjugates, especially the conjugation strategy that control the integrity, stability and release of siRNA bioconjugates. The limitations conferred by these conjugation strategies have also been covered.
RNA interference (RNAi), which is mediated by small interfering RNAs (siRNAs) derived from viral genome or its replicative intermediates, is a natural antiviral defense in plants, fungi, and ...invertebrates. Whether RNAi naturally protects humans from viral invasion is still a matter of debate. Nevertheless, exogenous siRNAs are able to halt viral infection in mammals. The current review critically evaluates the production of antiviral siRNAs, delivery techniques to the infection sites, as well as provides an overview of antiviral siRNAs in clinical trials.
Clinical advances of siRNA therapeutics Hu, Bo; Weng, Yuhua; Xia, Xin‐Hua ...
The journal of gene medicine,
July 2019, Letnik:
21, Številka:
7
Journal Article
Recenzirano
Small interfering RNA (siRNA) enables efficient target gene silencing by employing a RNA interference (RNAi) mechanism, which can compromise gene expression and regulate gene activity by cleaving ...mRNA or repressing its translation. Twenty years after the discovery of RNAi in 1998, ONPATTRO™ (patisiran) (Alnylam Pharmaceuticals, Inc.), a lipid formulated siRNA modality, was approved for the first time by United States Food and Drug Administration and the European Commission in 2018. With this milestone achievement, siRNA therapeutics will soar in the coming years. Here, we review the discovery and the mechanisms of RNAi, briefly describe the delivery technologies of siRNA, and summarize recent clinical advances of siRNA therapeutics.
siRNA holds tremendous promise to knockdown the disease-promoting gene in any cell type that it can be delivered. The biggest challenge facing the clinical translation of siRNA is to overcome the ...barriers that impede the in vivo delivery. siRNA is a highly hydrophilic macromolecule with poor pharmacological properties. The critical requirement for broadening the systemic siRNA delivery is to confer on siRNA the ‘drug-like’ properties such as the lipophilicity. In comparison with unmodified siRNA, lipophilic siRNA has a better cell-membrane compatibility and permeability. The lipophilic siRNA can also hijack the lipid trafficking pathway and natural drug carrier albumin to achieve an advanced systemic delivery, with properties including the tissue targeting, long circulation half-life, the improved pharmacokinetic profile, bioavailability and in vivo safety. In this review, we summarized the recent progress on lipophilic siRNA development, in particular about the chemical methods to manipulate siRNA lipophilicity. The covalent and noncovalent methodologies, including backbone modification, lipid conjugation, chelation method and others, are discussed. We place particular emphasis on the most clinically advanced method, the lipid siRNA conjugation. The application of lipophilic siRNA on nanoparticle delivery system is also covered.
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Secondary small interfering RNA (siRNA) production, triggered by primary small RNA targeting, is critical for proper development and antiviral defense in many organisms. RNA-dependent RNA polymerase ...(RDR) is a key factor in this pathway. However, how RDR specifically converts the targets of primary small RNAs into double-stranded RNA (dsRNA) intermediates remains unclear. Here, we develop an in vitro system that allows for dissection of the molecular mechanisms underlying the production of trans-acting siRNAs, a class of plant secondary siRNAs that play roles in organ development and stress responses. We find that a combination of the dsRNA-binding protein, SUPPRESSOR OF GENE SILENCING3; the putative nuclear RNA export factor, SILENCING DEFECTIVE5, primary small RNA, and Argonaute is required for physical recruitment of RDR6 to target RNAs. dsRNA synthesis by RDR6 is greatly enhanced by the removal of the poly(A) tail, which can be achieved by the cleavage at a second small RNA-binding site bearing appropriate mismatches. Importantly, when the complementarity of the base pairing at the second target site is too strong, the small RNA-Argonaute complex remains at the cleavage site, thereby blocking the initiation of dsRNA synthesis by RDR6. Our data highlight the light and dark sides of double small RNA targeting in the secondary siRNA biogenesis.
Summary
Like metazoans, plants use small regulatory RNAs (sRNAs) to direct gene expression. Several classes of sRNAs, which are distinguished by their origin and biogenesis, exist in plants. Among ...them, microRNAs (miRNAs) and trans‐acting small interfering RNAs (ta‐siRNAs) mainly inhibit gene expression at post‐transcriptional levels. In the past decades, plant miRNAs and ta‐siRNAs have been shown to be essential for numerous developmental processes, including growth and development of shoots, leaves, flowers, roots and seeds, among others. In addition, miRNAs and ta‐siRNAs are also involved in the plant responses to abiotic and biotic stresses, such as drought, temperature, salinity, nutrient deprivation, bacteria, virus and others. This review summarizes the roles of miRNAs and ta‐siRNAs in plant physiology and development.
Significance Statement
Plants use small regulatory RNAs (sRNAs) to control biological processes via repression of gene expression. Among them, microRNAs (miRNAs) and trans‐acting small interfering RNAs (ta‐siRNAs) mainly inhibit gene expression at post‐transcriptional levels. Here we review the function of miRNAs and siRNAs in plant development and in response to abiotic stresses and biotic interactions.
Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have ...progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types.
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Small interfering RNAs (siRNAs) have potential to silence virtually any disease-causing gene but require chemical modifications for delivery to the tissue and cell of interest. Previously, we ...demonstrated that asymmetric, phosphorothioate (PS)-modified, chemically stabilized, cholesterol-conjugated siRNAs, called hsiRNAs, support rapid cellular uptake and efficient mRNA silencing both in cultured cells and in vivo. Here, we systematically evaluated the impact of number, structure, and sequence context of PS-modified backbones on cellular uptake and RNAi-mediated silencing efficacy. We find that PS enhances cellular internalization in a sequence-dependent manner but only when present in a single-stranded but not double-stranded region. Furthermore, the observed increase in cellular internalization did not correlate with functional silencing improvement, indicating that PS-mediated uptake may drive compounds to non-productive sinks. Thus, the primary contributing factor of PS modifications to functional efficacy is likely stabilization rather than enhanced cellular uptake. A better understanding of the relative impact of different chemistries on productive versus non-productive uptake will assist in improved design of therapeutic RNAs.
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Ly et al. show that in the context of asymmetric, cholesterol-conjugated small interfering RNAs (siRNAs), phosphorothioate (PS)-modified backbones increase cellular uptake in cultured cells but do not necessarily improve silencing activity. Thus, the primary contributing factor of PS modifications to functional efficacy is likely stabilization rather than enhanced cellular uptake.
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