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Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Ramasamy Paulmurugan, Uday Kumar Sukumar, Tarik F. Massoud
MiRNAs are small single stranded RNAs of 18–23 nucleotides that are partially or fully complimentary to the 3’ non-coding region of target mRNA sequence. MiRNAs achieve gene silencing through blocking mRNA translation or by degrading target mRNAs. The ability to achieve sequence-specific gene silencing using RNAi (siRNA, shRNA, and miRNA) has been used in a wide range of applications, including the treatment of numerous diseases, particularly for the cancer therapy [91]. Nevertheless, in vivo systemic administration and delivery of the small silencing RNA-based therapeutics to cells and tumors remain a challenge, owing to limitations such as poor cellular uptake, degradation by serum nucleases, and rapid renal clearance after administration [92]. To overcome these limitations, the development of effective and safe nanocarriers for systemic delivery of small silencing RNAs is required for efficient cancer therapy. Biodegradable polymer nanoparticles have been found to be safe and effective nanocarriers for the delivery of small silencing RNAs and show promising translational clinical applications.
Infiltrative Diseases
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
TTR gene silencing, either through RNA interference or antisense oligonucleotides, is another treatment strategy for ATTR amyloidosis. Small interfering RNAs (siRNAs) are delivered to hepatocytes and target gene expression leading to the degradation of TTR mRNA. Patisiran, a siRNA, resulted in a dose-dependent reduction of serum TTR levels in patients with hATTR polyneuropathy. The phase III APOLLO study included 225 patients with hATTR polyneuropathy randomized to receive either patisiran infusions or placebo, and patisiran resulted in improvement in the neuropathy impairment score (NIS) after 18 months of therapy.57 In the pre-specified cardiac subgroup, consisting of patients with LV wall thickness ≥ 13 mm with no concomitant history of hypertension or valvular disease, patisiran resulted in an improvement in NT-proBNP, LV wall thickness, and global longitudinal strain.58
Human Bcl-2 Antisense Therapy for Lymphomas
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Finbarr E. Cotter, Andrew Webb, Paul Clarke, David Cunningham
The aim for antisense researchers is to show down-regulation of a gene in a sequence-specific manner while control oligonucleotides show little or no down-regulating capability. It follows that all antisense experiments must be interpreted with adequate reference to control parameters. Primarily it is essential to investigate the possibility of the AO having a non-sequence specific effect, which would negate its use for a true "gene silencing" strategy. Whatever the mechanism, the important consideration in assessing antisense effects is to establish sequence specificity of the AO against control oligomers, and to demonstrate a decrease in the amount of protein produced by the gene targeted. This has been demonstrated for G3139 and G3854 using both sense and nonsense controls. Downregulation of the Bcl-2 protein was demonstrated at 72 hours onwards in lymphoma cells with the t(l4; 18) translocation with antisense oligonucleotides but not with the control sense and nonsense oligonucleotides (Cotter et al., 1994). This result correlates with the Bcl-2 protein having a relatively long half-life. The effect was specific to cell lines dependent on Bcl-2 for survival. No nonspecific antiproliferative effects were seen (Cotter et al., 1994).
Metal nanoparticles as a promising technology in targeted cancer treatment
Published in Drug Delivery, 2022
Jia-Jie Xu, Wan-Chen Zhang, Ya-Wen Guo, Xiao-Yi Chen, You-Ni Zhang
The regulation of gene expression in a cell to prohibit the expression of a specific gene is known as gene silencing. Due to its potential to suppress genes implicated in tumor formation, gene silencing grasps promising cancer therapy gene silencing is the process of altering gene expression on an epigenetic level. This is accomplished mostly through the use of antisense DNA and short interfering RNA (Liu et al., 2019). Fernandes & Baptista (2017) reported gene silencing using multifunctional gold NPs for cancer therapy to improve tumor cell identification and uptake. Gold NPs' surfaces were functionalized using targeting peptides. This approach inhibits KRAS gene expression in colorectal cancer cell lines while leaving healthy fibroblasts unharmed. Gene silencing with small interfering RNA (siRNA) is another option. siRNAs can be delivered to cells by using a platelet cell membrane-coated metal (zinc)-organic framework (MOF). Using a simple one-pot method, synthetic siRNAs were loaded onto porous metal-organic framework (MOF) NPs. pH affects the structural integrity of MOF scaffolds. In vitro targeting and intracellular localization were performed on human SK-BR-3 breast cancer cells (HTB-30; American Type Culture Collection, Manassas, VA). To bind specifically to cancer cells, a platelet membrane coating was employed (Fernandes & Baptista, 2017).
Gene therapy to terminate tachyarrhythmias
Published in Expert Review of Cardiovascular Therapy, 2022
Kohei Kawajiri, Kensuke Ihara, Tetsuo Sasano
Gene silencing is a term used to describe technologies that suppress gene expression, including antisense oligonucleotide (ASO) and siRNA. Gene silencing is a strategy that affects post transcription, reducing expression of defective alleles or specific pathways. Gene silencing is a widely used method for analyzing gene function and is also being applied for therapeutic purposes. In addition to simple suppression of pathologically elevated gene expression and signaling pathways, it is possible to design allele-specific siRNA for mutant allele to suppress abnormal protein production with gain of function or dominant negative mutations. In the field of arrhythmia, gene silencing is expected to be applied especially to hereditary arrhythmias. Bongianino et al. demonstrated that the gene silencing approach has ameliorated pacing-induced VT in CPVT mice models [99]. In addition, the other study showed that allele-specific RNA silencing may be effective in treating hypertrophic cardiomyopathy and dilated cardiomyopathy [117]. These studies demonstrated the feasibility of allele-specific silencing as a treatment for inherited cardiac diseases via a single parenteral injection of the appropriate therapeutic construct [118]. There are other arrhythmias such as LQTS [119], which take the form of autosomal-dominant inheritance. It is expected that gene silencing will be used to develop treatments for these diseases.
Layer-by-Layer technique as a versatile tool for gene delivery applications
Published in Expert Opinion on Drug Delivery, 2021
Dmitrii S. Linnik, Yana V. Tarakanchikova, Mikhail V. Zyuzin, Kirill V. Lepik, Joeri L. Aerts, Gleb Sukhorukov, Alexander S. Timin
RNA interference has a wide application as a gene silencing strategy for the treatment of genetic and acquired diseases. Small interfering RNA (siRNA) is homologous to a specific target mRNA and is able to knock down its expression using cell-intrinsic mechanisms such as Dicer and RISC, thus causing a biological effect [81]. siRNA has important limitations in biomedical applications, which can be attributed to its hydrophilic nature, low inherent stability, and degradation in the bloodstream in the presence of nucleases: inefficient cellular uptake, cytotoxicity, and stimulation of immune responses. Viral vectors have been commonly used for siRNA delivery, which overcomes the problem of low transfection. However, viral vectors have several limitations, such as the need for active cell division for gene transduction, oncogenic potential, low titers, and gene silencing [82]. Therefore, the most important challenge for siRNA-mediated in vivo silencing is the development of safe (non-viral) delivery systems to deliver siRNAs into specific tissues and organs.