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Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Nyree Maes, Skye Zeller, Priti Kumar
The first clinical trial for gene therapy against HIV used a conditionally-replicating lentiviral vector expressing a LTR-driven long antisense RNA (asRNA), VRX494. This asRNA targeted a large sequence in the envelope gene and showed great promise in cell culture experiments. Mutant viruses generated contained large deletions in the envelope that resulted in a significant loss of fitness [60, 83]. A phase I nonrandomized clinical trial initiated in 2003 recruited five subjects with chronic drug resistant HIV who were transfused with ~10 billion VRX496 transduced autologous CD4+ T cells [76]. Despite low levels of long-term engraftment, three subjects showed strong decline in viral titers (0.75 log to 1.7 logs), four had elevated CD4+ T cell counts at 1 year following engraftment and three had elevated IFN-γ responses and increases in general immune function up to 2 years following treatment. The major safety concerns that were quelled by this study included integration site preferences (integration was random), emergence of replication-competent lentivirus (none was detected at any time point), and vector mobilization into non-target tissues (mobilization was transient and did not appear after day 60). Further clinical trials have been initiated including two phase II trials evaluating multiple doses or a higher single dose and one phase I/II trial, which will stop HAART on patients following infusion of VRX496 treated cells [113].
Elastic Liposomes for Drug Delivery
Published in Vladimir Torchilin, Handbook of Materials for Nanomedicine, 2020
Nicole J. Bassous, Amit K. Roy, Thomas J. Webster
The intracellular delivery of novel macromolecular drugs against viruses, including antisense oligodeoxynucleotides, ribozymes and therapeutic genes, may be achieved by encapsulation in or association with certain types of liposomes [88]. Liposomes may also protect these drugs against nucleases. Low-molecular-weight, charged antiviral drugs may also be delivered more efficiently via liposomes. Liposomes have been targeted to HIV-1-infected cells via covalently coupled soluble CD4 [88]. Human monocyte-derived macrophages produced less HIV-1 upon exposure to negatively charged multilamellar liposomes that were loaded with an HIV-1 protease inhibitor; in fact, the effect of the liposome-loaded drug was over ten times more potent than the free drug, and a lower EC90 was additionally observed. Alternatively, sterically stabilized liposomes that were loaded with the drug behaved just as well as the free drug. When delivered in pH-sensitive liposomes to HIV-2-infected macrophages, the reverse transcriptase inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) had an EC50 value that was one order of magnitude lower. HIV-1 replication in macrophages via the delivery of a 15-mer antisense oligodeoxynucleotide inside pH-sensitive liposomes was diminished, where generally this oligonucleotide displays little to no activity at restricting viral reproduction in its free form. Oligodeoxynucleotide-encapsulated liposomes with sterically stabilized and pH-responsive membranes were additionally developed by the authors, and their prolonged in vivo performance was exceptional.
Quantum Dots Designed for Biomedical Applications
Published in Claudia Altavilla, Enrico Ciliberto, Inorganic Nanoparticles: Synthesis, Applications, and Perspectives, 2017
Ragusa Andrea, Zacheo Antonella, Aloisi Alessandra, Pellegrino Teresa
Gene therapy is a method by which proper DNA sequences are inserted into target cells as corrective genetic material. On the other hand, at a posttranscriptional level, the delivery of short RNA sequences, so-called interference-RNA (RNAi), which inhibits gene expression (gene silencing) primarily by targeting messenger-RNA sequences (mRNAs), is exploited in short interfering RNA (siRNA) therapy. RNAi was first observed in the nematode worm Caenorhabditis elegans (Fire et al. 1998). RNAi has soon become a promising tool for sequence-specific gene silencing when Tushl et al. showed that RNAi in mammalian cells was mediated by 21-22-nucleotides RNA sequences (Elbashir et al. 2001). In recent years, this kind of therapeutic modality reaches particular relevance because it has the prospective to modulate “non-druggable” targets (Troy et al. 2004; Uprichard 2005; Dykxhoorn et al. 2006). A gene encoding the antisense RNA can be introduced into the cell organisms by using different vectors, including plasmid vector and lipofectamine.
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
The two platforms for translation inhibition are short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), both nucleic acid derivatives that harness natural cellular mechanisms to regulate the expression of host or viral messenger RNA transcripts. siRNAs are small double stranded RNA sequences typically 19–27 base pairs in length with an antisense strand that is complimentary to the unwanted mRNAs. After entering the hepatocytes, the siRNA duplex unwinds and is loaded into the cytoplasmic RNA-induced silencing complex (RISC). The antisense strand directs site-specific cleavage of the complementary target RNA sequence, resulting in RNA degradation, thereby silencing the parent gene. In contrast, ASOs are single-stranded oligonucleotides typically 18–30 base pairs in length. They hybridise directly with complementary mRNA and are destroyed through cytoplasmic RNase H-mediated cleavage.
Applications and hazards associated with carbon nanotubes in biomedical sciences
Published in Inorganic and Nano-Metal Chemistry, 2020
Ali Hassan, Afraz Saeed, Samia Afzal, Muhammad Shahid, Iram Amin, Muhammad Idrees
An important technique that makes use of antisense ODN to treat tumors and other genetic diseases is called antisense therapy. Antisense ODN inside the cells bind to the beginning location of target messenger RNA or transcriptional factors. This binding prevents the translation of that messenger RNA into protein and controls the expression of a gene at the translational level. CNTs have been proved to be an efficient carrier to deliver antisense ODN inside the cells both in vivo and in vitro.[69,70] In an experiment, CNTs coupled with antisense myc delivered in vitro to the human leukemia HL60 cells. This delivery inhibited the expression of the c-myc gene and slowed down the proliferation of HL60 cells and paved their way toward apoptosis. Thus, modified the expression of gene both at transcriptional as well as translational level.[70] MWCNTs coupled with antisense ODN along with quantum dots were administered into a human. These coupled CNTs entered into human cervical cancer cells through endocytosis and caused apoptosis of cancer cells.[71] One limitation associated with the use of ODN as gene therapy agent is lack of specificity. For that reason, approaches that use small RNA are preferred.
Potential strategies to prevent encrustations on urinary stents and catheters – thinking outside the box: a European network of multidisciplinary research to improve urinary stents (ENIUS) initiative
Published in Expert Review of Medical Devices, 2021
Ali Abou-Hassan, Alexandre Barros, Noor Buchholz, Dario Carugo, Francesco Clavica, Petra de Graaf, Julia de La Cruz, Wolfgang Kram, Filipe Mergulhao, Rui L Reis, Ilya Skovorodkin, Federico Soria, Seppo Vainio, Shaokai Zheng
Many pathogenic pathways depend on an insufficient or, to the contrary, excessive production of certain proteins [32]. More recently, antisense strategies were explored to address cancer, infectious diseases, chronic inflammatory diseases, and metabolic conditions [33]. Antisense technology is a method that interferes with protein production. It can therefore be used in diseases in which the over- or underproduction of a specific protein plays a crucial role. The principle is that an antisense nucleic acid sequence base pairs with its complementary sense RNA strand and prevents it from being translated into a protein [32] or interferes with its functional aspects [34]. Being a target-specific approach, it is highly attractive for treating underlying molecular disease pathways [33].