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Nucleic Acid Therapeutics

Yoshiaki Masaki, Yusuke Iriyama, Hiroyuki Nakajima, Yusuke Kuroda, Tatsuro Kanaki, Satoshi Furukawa, Mitsuo Sekine, Kohji Seio
An RNase H-dependent antisense oligonucleotide (ASO), having the 2'-O-(2-N-methylcarbamoylethyl) (MCE) modification, was evaluated in vitro and in vivo. The antisense activities of an ASO having the MCE modification were comparable with those of an ASO having the 2'-O-methoxyethyl (MOE) modification in both in vitro and in vivo experiments. In contrast, the hepatotoxic potential of the ASO having the MCE modification was lower than that of the ASO having the MOE modification. Thus, these findings suggested that the MCE modification could be used as an alternative to the MOE modification...
July 18, 2018: Nucleic Acid Therapeutics
Francesco Mainini, David S Larsen, Gill A Webster, Sarah L Young, Michael R Eccles
MIS416 is a microparticulate formulation derived from propionibacterium acnes cell wall skeletons with intrinsic adjuvant activity. Conjugates of MIS416-SS-peptide containing a disulfide linkage facilitate the cytoplasmic delivery and release of peptides in antigen-presenting cells (APCs). We hypothesized that MIS416-siRNA (small interfering RNA) conjugates, containing a disulfide linkage between MIS416 and the siRNA, would allow cytoplasmic release of siRNA in APCs. MIS416-SS-siStat3 conjugates added to cell culture medium of monolayers of DCs in culture flasks successfully targeted Stat3 mRNA in DCs in vitro without transfection, downregulating Stat3 mRNA and protein levels...
June 12, 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
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
Ludger Johannes, Marco Lucchino
RNA interference (RNAi) is a fundamental cellular process for the posttranscriptional regulation of gene expression. RNAi can exogenously be modulated by small RNA oligonucleotides, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), or by antisense oligonucleotides. These small oligonucleotides provided the scientific community with powerful and versatile tools to turn off the expression of genes of interest, and hold out the promise of new therapeutic solutions against a wide range of gene-associated pathologies...
June 2018: Nucleic Acid Therapeutics
Amy C Yan, Matthew Levy
Targeting cells with aptamers for the delivery of therapeutic cargoes, in particular oligonucleotides, represents one of the most exciting applications of the aptamer field. Perhaps nowhere has there been more excitement in the field than around the targeted delivery of siRNA or miRNA. However, when industry leaders in the field of siRNA delivery have tried to recapitulate aptamer-siRNA delivery results, they have failed. This problem stems from more than just the age-old problem of delivery to the cytoplasm, a challenge that has stymied the targeted delivery of therapeutic oligonucleotides since its inception...
June 2018: Nucleic Acid Therapeutics
Aaron D Springer, Steven F Dowdy
Short-interfering RNA (siRNA)-induced RNAi responses have great potential to treat a wide variety of human diseases from cancer to pandemic viral outbreaks to Parkinson's Disease. However, before siRNAs can become drugs, they must overcome a billion years of evolutionary defenses designed to keep invading RNAs on the outside cells from getting to the inside of cells. Not surprisingly, significant effort has been placed in developing a wide array of delivery technologies. Foremost of these has been the development of N-acetylgalactosamine (GalNAc) siRNA conjugates for delivery to liver...
June 2018: Nucleic Acid Therapeutics
Steven F Dowdy, Matthew Levy
No abstract text is available yet for this article.
June 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...
June 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...
June 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...
June 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...
June 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...
June 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...
June 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...
June 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
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
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...
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
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