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siRNA Delivery for Therapeutic Applications Using Nanoparticles
Published in Yashwant Pathak, Gene Delivery, 2022
The gene silencing mechanism is initiated by the RNAi process in which the enzyme dicer cleaves the double stranded RNAs into short double-stranded siRNAs of 21 to 25 nt [5]. The siRNA passenger strand is then unwound, and the guide strand of siRNA is loaded into the RNA-induced silencing (RISC) complex paired with the mRNA complementary sequence, causing cleavage of target mRNAs by Argonaute 2 (Ago2) (Figure 8.1). This important mechanism has allowed to open novel therapeutic approaches by designing oligonucleotide molecules through using mRNA transcripts sequences found in the existing human genomic data. Therefore, a careful sequence selection and synthesis of tailored siRNAs may have enormous repercussions in therapy, as almost all genes might be down-regulated, while splice variants, separate transcripts, or mutations might also be specifically targeted. As a consequence, this powerful approach might help circumvent the limitations exhibited by small molecule drugs in conventional cancer therapy treatments, leading to drug development processes based on gene functionality. Therefore, the development of this therapeutic strategy may have a high impact on modern medicine [5–7].
Role of Epigenetics in Immunity and Immune Response to Vaccination
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
miRNAs are transcribed by RNA polymerase II as a hairpin loop structure, called the pri-miRNA. Following transcription, pri-miRNAs are capped and polyadenilated (Cai, Hagedorn, and Cullen 2004). Pri-miRNAs undergo a nuclear processing where the pri-miRNA is cleaved by microprocessor complex, comprised of DiGeorge syndrome critical region 8 (DGCR8) and Drosha proteins (Gregoryi, Chendrimada, and Shiekhattar 2006; Conrad et al. 2014). The cleavage product is called a pre-miRNA. Nuclear processing is followed by the export of pre-miRNA to cytoplasm by Exportin. Pre-miRNA is cleaved by an enzyme called dicer to yield a double stranded miRNA complex. Following the cleavage by dicer, one strand of this miRNA duplex is loaded into the RNA-induced silencing complex (RISC) to interact with its target (Kim and Kim 2012; Park et al. 2011). Gene silencing by miRNAs has two modes depending on the miRNA target complementarity. Perfect or near perfect complementarity between the miRNA and its target mRNA induces the cleavage and degradation of target mRNA. In case of a non-perfect complementarity, the target mRNA is silenced through inhibition of translation (Lim et al. 2005).
Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Gene therapy is the use of genes as medicine that involves the transfer of a therapeutic or working gene (DNA and RNA) copy into specific cells of a patient in order to repair gene defects due to mutations [403–409, 413, 420–426]. This technique has been studied in clinical settings for a variety of cancer types and other disease involving gene defects. Cancer cells possess upregulated or inappropriately expressed genes, which leads to uncontrolled cell growth. Identification of target genes could lead to development of tailored anticancer agents with which the toxic side effect of cancer chemotherapies could be overcome. For example, RNAi-based gene therapies, i.e., sequence-specific post-transcriptional silencing of gene expression mediated by small double-stranded (dsRNA), have the potential to treat a variety of human genomic disorder, especially in combination with conventional therapies such as chemotherapy [419, 424]. Whereas knockdown of a target mRNA is not feasible with sense and antisense RNAs, dsRNA can lead to an effective and a specific mRNA knockdown. After dsRNA is introduced into cells it is cleaved by the enzyme dicer, a member of the RNaseIII family of dsRNA-specific ribonucleases [407, 409, 421, 424]. This enzymatic cleavage degrades the RNA to 19–23 bp duplexes, each with a 2-bp 3′ overhang [703, 408, 422].
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.
Pleuropulmonary Blastoma Developing in a Case of Misinterpreted Congenital Pulmonary Airway Malformation: a Case Report
Published in Fetal and Pediatric Pathology, 2018
Moupali Ghosh, Nelofar Islam, Arindam Ghosh, Priyanka Maity Chaudhuri, Koushik Saha, Uttara Chatterjee
There are several reports of PPB developing in a background of CPAM [2–5,21]. However, this association between PPB and CPAM has been questioned and redefined in a series of articles by Hill et al., Priest et al., and Dehner et al. [6–8]. From these clinicopathological studies, three important findings emerged. First, the pathogenesis of PPB is a continuum, where the mass stage (PPB type III) is preceeded by a multicystic stage (PPB type I), followed by a solid cystic neoplasm (type II). These three stages are considered as progressive morphologic stages in the pathogenesis of PPB. In the report of 50 cases, there was a remarkable correlation between the age at diagnosis and type of tumor which in turn correlated with the prognosis. The second observation was that many of these cases had a familial predisposition and were associated with inactivation of DICER 1 gene. Thirdly, a difficult problem in the diagnosis of type I PPB, was the coexistence of CPAM type IV in the same morphological spectrum as PPB type I.
Strategies for improving the specificity of siRNAs for enhanced therapeutic potential
Published in Expert Opinion on Drug Discovery, 2018
Aditya Kiran Gatta, Raghu Chandrashekhar Hariharapura, Nayanabhirama Udupa, Meka Sreenivasa Reddy, Venkata Rao Josyula
The RNA interference, as a concept, was first described by Napoli and his associates in 1990 from the experiments on petunia flowers and the phenomenon is known as co-suppression [3]. The experiments performed by Fire and Mello in 1998 in this niche area on Caenorhabditis elegans won the Noble Prize for them [4]. Later on, a team led by Elbashir et al. proved this concept in mammalian cell line models [5]. This generated tremendous interest among the cancer biologists in exploring its utility for cancer therapy. RNA interference downregulates the gene expression through binding with the messenger RNA (mRNA) by inhibition microRNA (mi-RNA) or by the degradation of mRNA, i.e. small interfering RNA (siRNA). As a result, translation of the mRNA is prevented. Hence, it is also known as Post Transcriptional Gene Silencing [6,7]. The Dicer is a large protein (Mol. wt. 220 kDa) with various functional domains. The double-stranded duplex RNA in the cell is processed by Dicer in association with double-stranded RNA binding proteins [8]. The Dicer produces 21–23 nucleotide sequence, which integrates with Argonaute (AGO2) to form a Ribosome-Induced Silencing Complex (RISC). From this sequence, the passenger strand is cleaved, and the guide strand is retained, which scans for its complementary mRNA sequence to pair with and cleaves in a perfect complementarity manner [9]. The initial step in developing RNAi therapeutics is the designing of siRNA, specifically binding to target mRNA and efficiently cleaving to prevent the translation step [10].