siRNA – AN EXCELLENT TECHNIQUE FOR DOWNREGULATION OF GENE EXPRESSION (original) (raw)
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International Journal of Biological Macromolecules, 2018
RNA interference (RNAi) therapy, harnessed to produce a new class of drugs for treatment, has drawn attention and seen steady progress over the years. Molecular therapy using biological macromolecules small interfering RNA (siRNA) for gene silencing has received significant attention to target cancer-related genes. Basically, siRNA molecules bind to messenger RNAs (mRNA) by complementary base pairing, to induce degradation of the mRNA and/or block protein synthesis. Numerous genes and gene related proteins have been reported till date to target in siRNA based cancer therapy. Furthermore, a combination of siRNA with traditional anticancer drugs produces synergistic anticancer effect, or overcomes drug resistance, enhances targeting abilities and minimizes side-effects. Current review highlights various functional properties of genes that can be selectively knocked down by siRNAs. In addition, we have also discussed the interaction of siRNA-mediated gene
RNA interference therapeutics for cancer: Challenges and opportunities (Review)
Molecular Medicine Reports, 2012
RNA interference (RNAi) is a sequence-specific, post-transcriptional gene silencing mechanism in animals and plants, which is mediated by double-stranded RNA (dsRNA). There has recently been an increasing interest in harnessing the gene silencing activity of dsRNA to develop novel drugs for the treatment of various diseases, such as cancer, neurological disorders, age-related macular degeneration and viral infections. Small interfering RNA (siRNA)-based drugs have distinct advantages over conventional small molecule or protein-based drugs, including high specificity, higher potency and reduced toxicity. However, there are several technical obstacles to overcome before siRNA-based drugs reach the clinic. Delivery of siRNA to the target tissues and stability in the serum remain a major challenge and are the main focus of current research and development efforts. This review focused primarily on the progress made in developing RNAi as therapeutics for cancer and the challenges associated with its clinical development. Use of ligands recognizing cell-specific receptors to achieve tumor-specific delivery of siRNA, methods for enhanced siRNA delivery, improving the bioavailability and pharmacokinetic properties of siRNA and reducing the off-target effects and non-specific gene silencing are discussed in the light of current evidence.
The silent treatment: siRNAs as small molecule drugs
Gene Therapy, 2006
As soon as RNA interference (RNAi) was found to work in mammalian cells, research quickly focused on harnessing this powerful endogenous and specific mechanism of gene silencing for human therapy. RNAi uses small RNAs, less than 30 nucleotides in length, to suppress expression of genes with complementary sequences. Two strategies can introduce small RNAs into the cytoplasm of cells, where they are active -a drug approach where doublestranded RNAs are administered in complexes designed for intracellular delivery and a gene therapy approach to express precursor RNAs from viral vectors. Phase I clinical studies have already begun to test the therapeutic potential of small RNA drugs that silence disease-related genes by RNAi. This review will discuss progress in developing and testing small RNAi-based drugs and potential obstacles.
Design of siRNA Therapeutics from the Molecular Scale
Pharmaceuticals, 2013
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.
RNAi through short interfering RNA (siRNAs) as a Novel Therapeutic Strategy
Since RNA interference (RNAi) was discovered in the late 1990s, it has evolved as a powerful and widely used strategy for the efficient silencing of genes. RNAi relies on the action of small interfering RNAs (siRNAs) which are incorporated into a complex termed RNA-induced silencing complex (RISC) and guide RISC to its cleavage site on the target mRNA. Thus, the efficiency of RNAi in vitro and in vivo is determined by the efficacy and intracellular presence of specific siRNA molecules. In vivo, the delivery of siRNAs is a major obstacle in the development of RNAi-based strategies also for clinical applications. Various approaches have been explored for the administration of RNAi in different pathological disorders. This review highlights criteria for the development of optimal siRNAs as well as strategies for siRNA stabilization and in vivo delivery. Different routes of siRNA administration and various siRNA formulations are discussed. The second part of the review provides a comprehensive overview on siRNA-mediated in vivo gene targeting in proof-of-principle studies as well as for the treatment of various pathologies including e.g. viral infection, cancer, liver and renal failure, CNS disorders and pathological ocular neovascularization.
Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach
Cancer is one of the most complex diseases that has resulted in multiple genetic disorders and cellular abnormalities. Globally, cancer is the most common health concern disease that is affecting human beings. Great efforts have been made over the past decades in biology with the aim of searching novel and more efficient tools in therapy. Thus, small interfering RNAs (siRNAs) have been considered one of the most noteworthy developments which are able to regulate gene expression following a process known as RNA interference (RNAi). RNAi is a post-transcriptional mechanism that involves the inhibition of gene expression through promoting cleavage on a specific area of a target messenger RNA (mRNA). This technology has shown promising therapeutic results for a good number of diseases, especially in cancer. However, siRNA therapeutics have to face important drawbacks in therapy including stability and successful siRNA delivery in vivo. In this regard, the development of effective siRNA delivery systems has helped addressing these issues by opening novel therapeutic windows which have allowed to build up important advances in Nanomedicine. In this review, we discuss the progress of siRNA therapy as well as its medical application via nanoparticle-mediated delivery for cancer treatment.
Indian Journal of Pharmacy and Drug Studies (IJPDS) , 2023
siRNA-mediated silencing of oncogenes holds great promise as a potential cancer therapy. By selectively silencing genes involved in cancer progression, siRNA-based therapies have the potential to be highly specific and effective, while minimizing off-target effects and toxicity. However, several challenges need to be addressed before siRNA-based therapies can be widely used in clinical settings. One of the major challenges is the development of efficient and safe delivery systems for siRNAs. Additionally, more clinical trials are needed to evaluate the safety and efficacy of siRNA-based therapies for cancer treatment. Despite these challenges, ongoing research and development in the field of siRNA-based therapies are promising. New delivery systems, personalized medicine approaches, and combination therapies are being explored, which could potentially lead to more effective and personalized cancer treatment. With continued research and development, it is hoped that siRNA-based therapies will eventually become cancer treatments, providing patients with a more targeted and effective treatment option.
Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice
Journal of Clinical Investigation, 2009
siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics. Conflict of interest: All authors are employees of Tekmira Pharmaceuticals Corp.
Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach
International Journal of Nanomedicine
Cancer is one of the most complex diseases that has resulted in multiple genetic disorders and cellular abnormalities. Globally, cancer is the most common health concern disease that is affecting human beings. Great efforts have been made over the past decades in biology with the aim of searching novel and more efficient tools in therapy. Thus, small interfering RNAs (siRNAs) have been considered one of the most noteworthy developments which are able to regulate gene expression following a process known as RNA interference (RNAi). RNAi is a post-transcriptional mechanism that involves the inhibition of gene expression through promoting cleavage on a specific area of a target messenger RNA (mRNA). This technology has shown promising therapeutic results for a good number of diseases, especially in cancer. However, siRNA therapeutics have to face important drawbacks in therapy including stability and successful siRNA delivery in vivo. In this regard, the development of effective siRNA delivery systems has helped addressing these issues by opening novel therapeutic windows which have allowed to build up important advances in Nanomedicine. In this review, we discuss the progress of siRNA therapy as well as its medical application via nanoparticle-mediated delivery for cancer treatment.