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  1. siRNA and RNAi optimization.
  2. Advanced Delivery and Therapeutic Applications of RNAi — Research Nebraska
  3. Advanced Delivery and Therapeutic Applications of RNAi
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His research interest includes delivery and targeting of small molecules, oligonucleotides, siRNA and genes. Kun Cheng , Ram I. Commonly used by researchers to develop technologies for modifying and studying genetic process, RNA interference RNAi has many potential uses in medicine, biotechnology, and functional genomics. This book covers all essential aspects involved in the development of RNAi therapeutics, providing detailed guidance on the challenges and opportunities of bringing RNAi technologies from bench to clinic.

It explores the design and mechanism of RNAi molecules, delivery strategies, and therapeutic applications in various diseases. Preclinical, regulatory, market, and intellectual aspects of RNAi technologies are also covered. RNAiD liv r r i. He is the author or co-author of 85 peer reviewed articles and book chapters. He is a Special Features Editor of Pharmaceutical Research and on the editorial board of several journals.

His research interest includes delivery and targeting of small molecules, oligonucleotides, siRNA and genes. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account.

If the address matches an existing account you will receive an email with instructions to retrieve your username. Skip to Main Content. First published: 26 April About this book Commonly used by researchers to develop technologies for modifying and studying genetic process, RNA interference RNAi has many potential uses in medicine, biotechnology, and functional genomics.


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This book covers all essential aspects involved in the development of RNAi therapeutics, providing detailed guidance on the challenges and opportunities of bringing RNAi technologies from bench to clinic. On the other hand, the focus has recently been on the non-viral approach because of its advantages over viral vectors, such as non-immunogenicity, low production cost and easy quality control. In cancer treatment, atelocollagen or cationic liposome- or polymer-mediated transfection reagents have commonly been used to deliver siRNA or miRNA to cells in vitro and in vivo.

In particular, a number of reports have demonstrated a significant anti-cancer effect caused by systemic delivery of siRNA with cationic liposome 39— In addition, atelocollagen can be obtained from type I collagen of calf dermis and has also been expected to be a useful carrier because of its low immunogenicity and efficiency 8 , 44— In case of miRNA therapy, a tumor-suppressive miR mimic was successfully delivered by the systemic approach using atelocollagen, and it dramatically inhibited the growth of metastatic prostate cancer Furthermore, chemically functionalized carbon nanotubes also show potential for novel biological applications for the delivery of Caspase-3 siRNA into the brain by topical injection into the cerebral cortex and reduced neurodegeneration without toxic side effects In a recent study, the focus was on highly stabilized nanoparticles, and these nanoparticles made the systemic delivery system dramatically more efficient 25 , 49— SNALP is a PEG-grafted monolamellar liposome that can easily avoid opsonization and subsequent recognition by the macrophages because the hydrophilic nature of PEG constructs an aqueous coating on its particle surface In the work of Judge et al.

Successful results have already been reported in the treatment of transthyretin-mediated amyloidosis, hypercholesterolemia, Ebola virus infection 49 and cancer Indeed, naked siRNAs are rapidly eliminated by the kidneys, and nanoparticle-formulated siRNAs have a tendency to accumulate in the liver.

In particular, their suitability for cancer cells depends on the enhanced permeability and retention effect of nanoparticles.

Lipid-Based Drug Delivery Systems

To solve these problems, combined use with orienting molecules, such as a cell-specific ligand, can increase the cell or tumor specificity and delivery efficiency 55— The TF receptors are known to be upregulated in malignant cells, and TF-stabilized particles are taken up into cancer cells by TF receptor-mediated endocytosis and subsequent release into the cytoplasm in a pH-dependent manner Delivery technology for RNAi therapy. The bilayer consists of cationic and neutral lipids and is coated by PEG.

RNAs are protected from degradation in serum by the cyclodextrin-conjugated polymer. In aqueous solution, adamantane easily binds to cyclodextrin as a result of hydrophobic attraction. In addition to the nanocarriers mentioned above, others are being sought through chemical modifications.

siRNA and RNAi optimization.

The purpose of such modifications can be permeability into the cells, specificity for specific tissues and stability against nuclease degradation Fig. For example, as a permeability-enhancing factor, the covalent conjugation of the lipophilic molecule assists siRNA or miRNA to penetrate into the cellular cytoplasm and trigger gene silencing in vivo The Arrowhead Research Corporation demonstrated that the co-injection of cholesterol-siRNA and hepatocyte-targeted endosomolytic polymer achieved high-level target gene knockdown with low doses of cholesterol-siRNA in non-human primates The company is using this strategy and a polymer-based siRNA delivery platform named dynamic polyconjugate polymer in ARC, which is a hepatitis B clinical candidate.

In another example, nanoparticles composed of poly lactic- co -glycolic acid were modified with a cell-penetrating peptide, penetratin, and used for the systemic delivery of the miR inhibitor in the mouse model of lymphoma Chemical modifications for stability. Sugar, backbone and base modifications are illustrated. On the other hand, cell-specific factors, such as aptamers 65 , 66 , peptide 64 , 67 , antibodies 68 , 69 and agonists 56 , can enhance cell specificity in cases of systemic administration into experimental animals.

For example, octaarginine-modified liposomal particles were used to suppress an endogenous gene in the liver at low concentrations of siRNA without any toxicity Usually, targeting proteins were conjugated to cationic bridges, such as polylysine or protamine, which can mediate uptake of nucleic acids, to link targeting proteins to effector oligonucleotide 68 , 70— In contrast, the siRNA-aptamer chimeras have also been of interest because a completely RNA-based approach may have important advantages over other methods for targeted delivery of siRNAs in terms of cost, productivity, safety and flexibility regarding chemical modification.

Advanced Delivery and Therapeutic Applications of RNAi — Research Nebraska

RNA aptamers are single-stranded oligonucleotides and bind with high affinity to specific molecular targets, such as small molecules, proteins and nucleic acids, with their 3D structure 65 , Here, although antibody-mediated siRNA delivery is required for the biological production of antibodies and antibody-siRNA conjugations by using a linker such as PEG, chimeric aptamer-siRNA can be synthesized as a single unit at once. However, for the utilization of chimeric aptamer-siRNA, more structured RNAs capable of binding with higher affinity and specificity have been required.

Stabilization in serum has been developed for the inhibition of the nuclease activity.


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  • Currently, the most consequential modification is the PS inter-nucleotide linkages that have been developed in the history of anti-sense oligonucleotides and have contributed to remarkable stabilization of double-strand RNA as well as the single-strand oligonucleotide 75 , However, the influence of chirality in the phosphorus atom on the stability and the activity of duplexes is not entirely understood. Therefore, further investigation of the thermodynamic features and physiological activity with regard to the assignment of the absolute configuration will be required for therapeutic applications.

    As reported above, a number of chemical modifications have been produced, which have enhanced the potential of siRNA, miRNA, miRNA inhibitors and anti-sense oligonucleotides.

    However, it has been required that the optimization of the modifications need to be optimized, as their efficiency depends on the position and combination. In , chemical modifications were optimized for single-stranded siRNAs ss-siRNAs , and the change was an important advancement for the practical application of RNAi therapeutics.

    Advanced Delivery and Therapeutic Applications of RNAi

    Furthermore, chemically modified ss-siRNAs targeting mutant huntingtin mRNAs have been employed as a novel nucleic acid drug for therapeutic application for Huntington's disease Although single-stranded RNAs ssRNAs have been shown to have extremely rapid degradation in serum and poor activities so far 78 , 79 , they have advantages, such as the absence of risk of undesirable off-target effects by passenger strand and the potential of systemic delivery without complex lipid formulations that sometimes trigger the inflammatory toxicities The alterations of miRNA expression profiling are significantly related with cancer initiation and progression.

    To identify dysregulated miRNAs in the physiological and pathological pathway of cancer malignancy is the first step for therapeutic applications. Generally, the widespread disruption of miRNAs is caused by at least three different mechanisms: the loss, amplification or mutation of a fragile cancer-related genomic region; the change of epigenetic control; and the abnormality of miRNA-processing steps. For instance, a significant downregulation of miR and miR, which is caused by deletion or mutation in chromosome 13q For example, miRa that regulates the expression of cyclin D kinase 6 was located in three chromosome loci, 8p In addition to genetic and epigenetic validation, alterations of the protein machinery related to the biogenesis of miRNA might impair global miRNA expression.

    According to one estimate, the widespread downregulation of the miRNA expression levels is prevalent in several cancer types 90 , In contrast, a kind of multi-functional polyphenolic compound, resveratrol, which is present in red wine, induced widespread upregulation of miRNAs and inhibited tumor growth through the acceleration of the expression and activity of Ago2 Thus, the observation and management of the total balance of miRNAs are important for cancer diagnosis and treatment.

    For the therapeutic applications of miRNA, the intracellular expression levels of miRNAs have to be artificially controlled. Although it is relatively easy to upregulate miRNAs, the strategy for the downregulation of miRNAs requires a refined miRNA inhibitor such as a chemically modified anti-sense oligonucleotide.

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    This conformational change contributes to a more efficient stacking of the nucleobases and functional inhibition of target miRNAs In therapeutic applications, LNA against the liver-expressed miR, which is a potential therapeutic target in the hepatitis C virus HCV , accomplished the long-lasting reduction of mature miR and suppression of HCV viremia 94 , However, antagomirs were excluded as clinical candidates because they were less effective than other miRNA inhibitors. PNAs are replaced its sugar-phosphate backbone to N - 2-aminoethyl glycine units, also have a potential to inhibit miRNA activities.

    For example, miRa, which is one of the best-studied tumor-suppressive miRNAs, was a therapeutic target in solid tumor treatment by Mirna Therapeutics and Regulus Therapeutics. The reduction of miRa by CpG methylation is observed in multiple types of cancer. The restoration of miRs has the potential to cause cell cycle arrest, senescence and apoptosis Mirna Therapeutics has also been conducting pre-clinical trials with miR and let-7 mimics, which are potent tumor-suppressive miRNAs 47 , , Furthermore, pre-clinical trials of miRNA inhibitors against miR and miRb, which are targeted as onco-miRs in hepatocellular carcinoma and glioblastoma, are being conducted.

    In addition to these developments, a number of non-public candidates for miRNA therapy are being considered by Mirna Therapeutics; they include miR-Rx01, 02, 03, 06 and Thus, miRNA therapeutics using miRNA mimics or inhibitors has been growing in pre-clinical studies and might appear in clinical trials over the next several years.

    RNAi is one of the most versatile knockdown tools in recent biotechnology, and the potential of RNAi therapeutics using miRNA for cancer treatment has been rapidly expanding. In particular, unlike siRNAs as a tool that specifically impairs the function of a target gene, miRNAs work as key regulators that control target genes and establish balanced cellular organization. Indeed, the disruption of such a balance leads to the possibility of a tumor to become malignant ,