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Nucleic Acid Therapeutics

Steven F Dowdy, Matthew Levy
No abstract text is available yet for this article.
May 21, 2018: Nucleic Acid Therapeutics
Maire F Osborn, Anastasia Khvorova
RNA interference (RNAi)-based therapeutics are approaching clinical approval for genetically defined diseases. Current clinical success is a result of significant innovations in the development of chemical architectures that support sustained, multi-month efficacy in vivo following a single administration. Conjugate-mediated delivery has established itself as the most promising platform for safe and targeted small interfering RNA (siRNA) delivery. Lipophilic conjugates represent a major class of modifications that improve siRNA pharmacokinetics and enable efficacy in a broad range of tissues...
May 10, 2018: Nucleic Acid Therapeutics
José J Pérez-Trujillo, Olivia A Robles-Rodríguez, Rodolfo Garza-Morales, Aracely García-García, Humberto Rodríguez-Rocha, Arnulfo Villanueva-Olivo, Juan C Segoviano-Ramírez, Sandra C Esparza-González, Odila Saucedo-Cárdenas, Roberto Montes-de-Oca-Luna, María J Loera-Arias
Directing an antigen to the endoplasmic reticulum (ER) improves the antigen-specific immune response, revealing a potentially useful strategy in cancer immunotherapy using tumor-associated antigens (TAAs). This can be achieved by fusing the antigen to an ER chaperone protein, such as calreticulin (CRT). We previously reported the antitumor response by fusing the CRT signal peptide (SP) and its ER retention sequence (KDEL) to full-length human papillomavirus type 16 (HPV-16) E6 and E7 antigens, obtaining a potent antitumoral effect...
May 7, 2018: Nucleic Acid Therapeutics
Louis Chonco, Gerónimo Fernández, Rahul Kalhapure, María J Hernáiz, Cecilia García-Oliva, Victor M Gonzalez, M Elena Martín, Thirumala Govender, Raveen Parboosing
The chemokine (C-C motif) ligand 21 (CCL21) is a cytokine that attracts CCR7-positive cells to the T cell (paracortical) zone of lymph nodes by directional migration of these cells along the CCL21 gradient. In this article, we sought to mimic this chemotactic mechanism, by identifying a novel aptamer that binds CCL21 with high affinity. In vitro selection of DNA aptamers was performed by the Systematic Evolution of Ligands by Exponential Enrichment. Quantitative polymerase chain reaction (qPCR) and enzyme-linked oligonucleotide assay were used to screen for high-affinity aptamers against human and mouse CCL21 protein, respectively...
May 7, 2018: Nucleic Acid Therapeutics
Johannes Winkler
Although recent clinical successes of antisense, splice-switching, and siRNA oligonucleotides have established the therapeutic utility of this novel class of medicines, the efficient systemic application for non-liver targets remains elusive. Exploitation of active receptor-mediated targeting followed by efficient and productive cellular uptake is required for enabling the therapy of extrahepatic diseases on the expressional level. Evasion of liver accumulation and organ-specific targeting and also efficient cytosolic delivery after endosomal internalization are currently insufficiently solved issues...
May 7, 2018: Nucleic Acid Therapeutics
Thomas A Zanardi, Tae-Won Kim, Lijiang Shen, David Serota, Chris Papagiannis, Shin-Young Park, Yunlip Kim, Scott P Henry
Advances in antisense oligonucleotide (ASO) chemistry and screening have enabled the design and selection of molecules that are optimized for a particular therapeutic application in terms of both potency and tolerability. The most-well studied of the chemically modified ASOs are single-stranded antisense inhibitors with phosphorothioate backbones and 2'-O-methoxyethyl modifications (2'-MOE ASO). The 2'-MOE chemical modification in the design of the ASO has conferred increased hybridization affinity, increased stability, and/or enhanced tissue residence time, resulting in better potency and pharmacokinetics...
April 30, 2018: Nucleic Acid Therapeutics
R L Juliano
Understanding the cellular uptake and intracellular trafficking of oligonucleotides provides an important basic underpinning for the developing field of oligonucleotide-based therapeutics. Whether delivered as "free" oligonucleotides, as ligand-oligonucleotide conjugates, or in association with various nanocarriers, all forms of oligonucleotide enter cells by endocytosis and are initially ensconced within membrane-limited vesicles. Accordingly, the locus and extent of release to the cytosol and nucleus are key determinants of the pharmacological actions of oligonucleotides...
April 30, 2018: Nucleic Acid Therapeutics
Matthew G Stanton
Messenger RNA is emerging as a highly versatile biological construct for creation of impactful medicines. mRNA vaccines directed toward infectious disease and cancer are in clinical development with encouraging early reads on tolerability and efficacy. The use of mRNA to direct intense but transient expression of paracrine factors is finding utility in reprogramming progenitor cells for wound healing and cardiac regeneration and for stimulation of antitumor immune responses, at least preclinically as we await clinical results...
April 24, 2018: Nucleic Acid Therapeutics
Jayesh A Kulkarni, Pieter R Cullis, Roy van der Meel
Genetic drugs based on RNA or DNA have remarkable therapeutic potential as virtually any disease can be treated by silencing a pathological gene, expressing a beneficial protein, or by editing defective genes. However, therapies based on nucleic acid polymers require sophisticated delivery systems to deliver these macromolecules to the interior of target cells. In this study, we review progress in developing nonviral lipid nanoparticle (LNP) delivery systems that have attractive properties, including ease of manufacture, reduced immune responses, multidosing capabilities, larger payloads, and flexibility of design...
April 23, 2018: Nucleic Acid Therapeutics
Yi Liu, Zhen Hua Chia, Johannes Nathaniel Min Hui Liew, Shi Min Or, Kyle K L Phua
Translation of in vitro transcribed messenger RNA (mRNA) is known to be compromised by cell's innate immune responses. Herein we show that when mRNA encoding nonstructural protein 1 (NS1), an immune evasion gene derived from influenza A virus, is co-delivered with mRNA encoding green fluorescent protein (GFP), higher GFP expression can be observed in four different interferon competent cell types within 6 h, indicating NS1's wide host range property and rapid counter response to the cells' innate immune response...
April 10, 2018: Nucleic Acid Therapeutics
Pooja Dua, Sinae Kang, Hye-Soo Shin, Soyoun Kim, Dong-Ki Lee
Increased interest and insights gained by researchers on the roles of endothelial cells in the pathophysiology of cancer, inflammatory, and cardiovascular diseases have led to the design of pharmacological interventions aimed at the endothelium lining in the diseased sites. Toward this end, we used established brain microvascular endothelial cell lines mouse (bEND3), human (hCMEC/D3), and Toggle Cell-SELEX to identify a species cross-reactive, endothelial cell-internalizing aptamer R11-3. This 2'F-modified RNA aptamer is specific for endothelial cells as no internalization was seen with cells of nonendothelial origin...
April 2, 2018: Nucleic Acid Therapeutics
Rahul R Nikam, Kiran R Gore
Since the evolutionary discovery of RNA interference and its utilization for gene knockdown in mammalian cell, a remarkable progress has been achieved in small interfering RNA (siRNA) therapeutics. siRNA is a promising tool, utilized as therapeutic agent against various diseases. Despite its significant potential benefits, safe, efficient, and target oriented delivery of siRNA is one of the major challenges in siRNA therapeutics. This review covers major achievements in clinical trials and targeted delivery of siRNAs using various targeting ligand-receptor pair...
March 27, 2018: Nucleic Acid Therapeutics
Lodewijk J A Toonen, João Casaca-Carreira, Maria Pellisé-Tintoré, Hailiang Mei, Yasin Temel, Ali Jahanshahi, Willeke M C van Roon-Mom
Antisense oligonucleotides (AONs) are versatile molecules that can be used to modulate gene expression by binding to RNA. The therapeutic potential of AONs appears particularly high in the central nervous system, due to excellent distribution and uptake in brain cells, as well as good tolerability in clinical trials thus far. Nonetheless, immune stimulation in response to AON treatment in the brain remains a concern. For this reason we performed RNA sequencing analysis of brain tissue from mice treated intracerebroventricularly with phosphorothioate, 2'-O-methyl modified AONs...
March 22, 2018: Nucleic Acid Therapeutics
Willeke M C van Roon-Mom, Raymund A C Roos, Susanne T de Bot
On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data...
April 2018: Nucleic Acid Therapeutics
Jeremiah D Farelli, Kirtika H Asrani, Cleo Isaacs, Joanna S deBear, Mary R Stahley, Anumeha Shah, Melissa A Lasaro, Christopher J Cheng, Romesh R Subramanian
Messenger RNA (mRNA) is a promising new class of therapeutics that has potential for treatment of diseases in fields such as immunology, oncology, vaccines, and inborn errors of metabolism. mRNA therapy has several advantages over DNA-based gene therapy, including the lack of the need for nuclear import and transcription, as well as limited possibility of genomic integration. One drawback of mRNA therapy, especially in cases such as metabolic disorders where repeated dosing will be necessary, is the relatively short in vivo half-life of mRNA (∼6-12 h)...
April 2018: Nucleic Acid Therapeutics
Colton M Miller, W Brad Wan, Punit P Seth, Edward N Harris
Second-generation (Gen 2) Antisense oligonucleotides (ASOs) show increased nuclease stability and affinity for their RNA targets, which has translated to improved potency and therapeutic index in the clinic. Gen 2 ASOs are typically modified using the phosphorothioate (PS) backbone modification, which enhances ASO interactions with plasma, cell surface, and intracellular proteins. This facilitates ASO distribution to peripheral tissues and also promotes cellular uptake after injection into animals. Previous work identified that Stabilin receptors specifically internalize PS-ASOs in the sinusoidal endothelial cells of the liver and the spleen...
April 2018: Nucleic Acid Therapeutics
Diana Gabriela Valencia-Reséndiz, Giovanni Palomino-Vizcaino, Juana Virginia Tapia-Vieyra, María Luisa Benítez-Hess, Ana Gabriela Leija-Montoya, Luis Marat Alvarez-Salas
Human papillomavirus type 16 (HPV16) DNA has been found in ∼50% of cervical tumors worldwide. HPV infection starts with the binding of the virus capsid to heparan sulfate (HS) receptors exposed on the surface of epithelial basal layer keratinocytes. Previously, our group isolated a high-affinity RNA aptamer (Sc5c3) specific for HPV16 L1 virus-like particles (VLPs). In this study, we report the inhibition of HPV16 infection by Sc5c3 in a pseudovirus (PsVs) model. 293TT cells were infected by HPV16 PsVs containing the yellow fluorescent protein (YFP) as reporter gene...
April 2018: Nucleic Acid Therapeutics
Colton M Miller, Michael Tanowitz, Aaron J Donner, Thazha P Prakash, Eric E Swayze, Edward N Harris, Punit P Seth
Oligonucleotide therapeutics have emerged as a third distinct platform for drug discovery within the pharmaceutical industry. Five oligonucleotide-based drugs have been approved by the US FDA and over 100 oligonucleotides drugs are currently at different stages of human trials. Several of these oligonucleotide drugs are modified using the phosphorothioate (PS) backbone modification where one of the nonbridging oxygen atoms of the phosphodiester linkage is replaced with sulfur. In this review, we summarize our knowledge on receptor-mediated uptake of PS antisense oligonucleotides (ASOs) within different cell types of the liver-a privileged organ for the discovery of oligonucleotide-based therapeutics...
February 9, 2018: Nucleic Acid Therapeutics
Fumito Wada, Tsuyoshi Yamamoto, Tetsuya Ueda, Motoki Sawamura, Shunsuke Wada, Mariko Harada-Shiba, Satoshi Obika
Recently, some studies have reported nephrotoxicity associated with a certain class of antisense oligonucleotides (ASOs) in humans. One possibility for reducing the potential nephrotoxicity of ASOs is to alter their pharmacokinetics. In this study, we investigated the effect of a ligand conjugation strategy on the renal accumulation of ASOs. We selected two ligands, cholesterol and N-acetylgalactosamine (GalNAc), with the purpose of reducing renal distribution and liver targeting, and then designed a series of cholesterol-GalNAc dual conjugated ASOs...
February 2018: Nucleic Acid Therapeutics
Danielle Vlaho, Johans F Fakhoury, Masad J Damha
A series of siRNA duplexes containing cationic non-bridging 3',5'-linked phosphoramidate (PN) linkages was designed and synthesized using a combination of phosphoramidite and H-phosphonate chemistries. Modified oligonucleotides were assayed for their thermal stability, helical structure, and ability to modulate the expression of firefly luciferase. We demonstrate that PN modifications of siRNAs are, in general, minimally destabilizing with respect to duplex thermal stability; destabilization can be mitigated through the incorporation of 2'-modified RNA-like residues or PN conjugates containing ionizable pendant moieties...
February 2018: Nucleic Acid Therapeutics
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