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Nucleic Acid Therapeutics

Jiaxin Hu, Xiulong Shen, Frank Rigo, Thahza P Prakash, V Vinod Mootha, David R Corey
Fuchs' endothelial corneal dystrophy (FECD) leads to vision loss and is one of the most common inherited eye diseases. Corneal transplants are the only curative treatment available, and there is a major unmet need for treatments that are less invasive and independent of donor tissue. Most cases of FECD are associated with an expanded CUG repeat within the intronic region of TCF4 and the mutant RNA has been implicated as the cause of the disease. We previously presented preliminary data suggesting that single-stranded antisense oligonucleotides (ASOs) can inhibit CUG RNA foci in patient-derived cells and tissue...
January 24, 2019: Nucleic Acid Therapeutics
Anjli Kukreja, Melissa Lasaro, Christian Cobaugh, Chris Forbes, Jian-Ping Tang, Xiang Gao, Cristina Martin-Higueras, Angel L Pey, Eduardo Salido, Susan Sobolov, Romesh R Subramanian
Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. Loss of alanine glyoxylate aminotransferase (AGT) function to convert intermediate metabolite glyoxylate to glycine causes the accumulation and reduction of glyoxylate to glycolate, which eventually is oxidized to oxalate. Excess oxalate in PH1 patients leads to the formation and deposition of calcium oxalate crystals in the kidney and urinary tract. Oxalate crystal deposition causes a decline in renal function, systemic oxalosis, and eventually end-stage renal disease and premature death...
January 24, 2019: Nucleic Acid Therapeutics
Maaike van Putten, Christa Tanganyika-de Winter, Sieto Bosgra, Annemieke Aartsma-Rus
Duchenne muscular dystrophy is a severe, progressive muscle-wasting disease that is caused by mutations that abolish the production of functional dystrophin protein. The exon skipping approach aims to restore the disrupted dystrophin reading frame, to allow the production of partially functional dystrophins, such as found in the less severe Becker muscular dystrophy. Exon skipping is achieved by antisense oligonucleotides (AONs). Several chemical modifications have been tested in nonclinical and clinical trials...
January 23, 2019: Nucleic Acid Therapeutics
Roel Bijkerk, Jonathan L S Esguerra, Johanne H Ellenbroek, Yu Wah Au, Maaike A J Hanegraaf, Eelco J de Koning, Lena Eliasson, Anton Jan van Zonneveld
Dysfunctional insulin secretion is a hallmark of type 2 diabetes (T2D). Interestingly, several islet microRNAs (miRNAs) are upregulated in T2D, including miR-132. We aimed to investigate whether in vivo treatment with antagomir-132 lowers expression of miR-132 in islets thereby improving insulin secretion and lowering blood glucose. Mice injected with antagomir-132 for 24 h, had reduced expression of miR-132 expression in islets, decreased blood glucose, and increased insulin secretion. In isolated human islets treated with antagomir-132, insulin secretion from four of six donors increased...
January 23, 2019: Nucleic Acid Therapeutics
Stanley T Crooke, Brenda F Baker, Shuting Xia, Rosie Z Yu, Nicholas J Viney, Yanfeng Wang, Sotirios Tsimikas, Richard S Geary
Advances in medicinal chemistry have produced new chemical classes of antisense oligonucleotides (ASOs) with enhanced therapeutic properties. Conjugation of the triantennary N-acetylgalactosamine (GalNAc3 ) moiety to the extensively characterized phosphorothioate (PS)-modified 2'-O-methoxyethyl (2'MOE) ASO exemplifies such an advance. This structure-activity optimized moiety effects receptor-mediated uptake of the ASO prodrug through the asialoglycoprotein receptor 1 to support selective targeting of RNAs expressed by hepatocytes...
December 20, 2018: Nucleic Acid Therapeutics
Ivan V Chernikov, Daniil V Gladkikh, Mariya I Meschaninova, Ulyana A Karelina, Alya G Ven'yaminova, Marina A Zenkova, Valentin V Vlassov, Elena L Chernolovskaya
The objective of this study was to analyze the effects of fluorophores on the intracellular accumulation and biological activity of small interfering RNA (siRNA) and its cholesterol conjugates. In this study, we used stem-loop real-time PCR and calibration curves to quantitate cellular siRNA accumulation. Attachment of fluorophores significantly affected both the accumulation and biological activity of siRNA conjugates. The severity of this effect depended significantly on the structure of the conjugate; fluorophores (Cy5...
December 18, 2018: Nucleic Acid Therapeutics
Manisit Das, Sara Musetti, Leaf Huang
Nucleic acid-based therapeutics like synthetic small interfering RNAs have been exploited to modulate gene function, taking advantage of RNA interference (RNAi), an evolutionally conserved biological process. Recently, the world's first RNAi drug was approved for a rare genetic disorder in the liver. However, there are significant challenges that need to be resolved before RNAi can be translated in other genetic diseases like cancer. Current drug delivery platforms for therapeutic silencing RNAs are tailored to hepatic targets...
December 18, 2018: Nucleic Acid Therapeutics
Margaret J Lange, Donald H Burke, John C Chaput
Recent advances in synthetic biology have led to the development of nucleic acid polymers with backbone structures distinct from those found in nature, termed xeno-nucleic acids (XNAs). Several unique properties of XNAs make them attractive as nucleic acid therapeutics, most notably their high resistance to serum nucleases and ability to form Watson-Crick base pairing with DNA and RNA. The ability of XNAs to induce immune responses has not been investigated. Threose nucleic acid (TNA), a type of XNA, is recalcitrant to nuclease digestion and capable of undergoing Darwinian evolution to produce high affinity aptamers; thus, TNA is an attractive candidate for diverse applications, including nucleic acid therapeutics...
December 11, 2018: Nucleic Acid Therapeutics
Annemieke Aartsma-Rus, Nathalie Goemans
Eteplirsen was approved for the treatment of eligible patients with Duchenne muscular dystrophy (DMD) in September 2016 in one of the most, if not the most, controversial approvals ever made by the Food and Drug Administration of the United States. Two years later, the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency gave a negative opinion for eteplirsen treatment. They had done so as well in May 2018, after which Sarepta (the company developing eteplirsen) appealed and a new evaluation was initiated, including a Scientific Advisory Group (SAG) meeting involving DMD experts and patient representatives...
December 11, 2018: Nucleic Acid Therapeutics
Shin-Ichiro Hori, Yasunori Mitsuoka, Akira Kugimiya
Antisense oligonucleotides (ASOs) are classified into gapmer and non-gapmer types according to their chemical modification pattern and mechanism of action. Although gapmer ASOs effectively reduce target RNA expression through intracellular RNase H1, high-affinity gapmer ASOs also have hepatotoxic potential. Non-gapmer ASOs, which are mainly used for pre-mRNA splicing regulation or functional inhibition of microRNA through their steric effects, are also able to inhibit target RNA expression using nonsense-mediated decay...
December 1, 2018: Nucleic Acid Therapeutics
Himani Sharma, Aarti Tripathi, Bharti Kumari, Sudhanshu Vrati, Arup Banerjee
Artificial microRNA (amiRNA)-mediated inhibition of viral replication has recently gained importance as a strategy for antiviral therapy. In this study, we evaluated the benefit of using the amiRNA vector against Japanese encephalitis virus (JEV). We designed three single amiRNA sequences against the consensus sequence of 3' untranslated region (3'UTR) of JEV and tested their efficacy against cell culture-grown JEV Vellore strain (P20778) in neuronal cells. The binding ability of three amiRNAs on 3'UTR region was tested in vitro in HEK293T cells using a JEV 3'UTR tagged with luciferase reporter vector...
November 20, 2018: Nucleic Acid Therapeutics
Joanna Fafińska, Andreas Czech, Tobias Sitz, Zoya Ignatova, Ulrich Hahn
Cluster of differentiation 24 (CD24) is a cell surface glycoprotein, which is largely present on hematopoietic cells and many types of solid tumor cells. CD24 is known to be involved in a wide range of downstream signaling pathways and neural development, yet the underlying mechanisms are poorly understood. Moreover, its production correlates with poor cancer prognosis, and targeting of CD24 with different antibodies has been shown to inhibit disease progression. Nucleic acid aptamers are oligonucleotides that are selected from random DNA or RNA libraries for high affinity and specific binding to a certain target...
November 8, 2018: Nucleic Acid Therapeutics
Rasmus Jansson-Löfmark, Peter Gennemark
Knowledge of the kinetics of the active drug in biophase, that is, at the effect site, is fundamental to select dose and to reason about safety. Unfortunately, the kinetics is cumbersome to measure in vivo. We describe how dose-response-time (DRT) analysis estimates the biophase and the target-response half-lives from data of the circulating protein of the encoded messenger RNA for seven antisense oligonucleotides (ASOs) and four small interfering RNA (siRNA) drugs. The biophase half-lives were estimated with acceptable precision (relative standard error <26%)...
October 31, 2018: Nucleic Acid Therapeutics
Markus Denzinger, Antonia Link, Julia Kurz, Sabrina Krauss, Robert Thoma, Christian Schlensak, Hans Peter Wendel, Stefanie Krajewski
Keratinocyte growth factor (KGF) plays a central role in wound healing as it induces cell proliferation and motility. The use of growth factors such as KGF is therefore viewed as a promising approach in wound therapy, although effective application remains a major problem because of inactivation and the resulting short half-life of applied growth factors in wound beds. Therefore, the rational of this study was to develop and investigate an innovative strategy to improve wound healing using an in vitro-transcribed modified KGF messenger RNA (mRNA)...
October 30, 2018: Nucleic Acid Therapeutics
Michael J Gait, Andrey A Arzumanov, Graham McClorey, Caroline Godfrey, Corinne Betts, Suzan Hammond, Matthew J A Wood
The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs...
October 16, 2018: Nucleic Acid Therapeutics
Aaron J Donner, Thomas A Bell, Sarah Greenlee, Mark J Graham, Rosanne M Crooke
To determine if the pharmacokinetics and pharmacodynamics of gapmer antisense oligonucleotides (ASOs), containing phosphorothioate backbones and 2'-O-methoxyethyl RNA modifications (2'-MOE ASOs), can be altered by renal disease, a series of experiments were performed in models of chronic kidney disease (CKD) and acute kidney injury (AKI). In an adenine diet model of CKD, 2'-MOE ASO activity in the whole kidney was preserved and the reduction in target RNA was sustained for 2-4 weeks postdose. Additionally, 2'-MOE ASO distribution within the kidney was altered in mice with CKD, in that ASO delivery to cortical regions with tubular damage was reduced while distribution to the medulla was increased...
October 2018: Nucleic Acid Therapeutics
Jessica Chery, Andreas Petri, Alexandre Wagschal, Sun-Young Lim, James Cunningham, Shobha Vasudevan, Sakari Kauppinen, Anders M Näär
The Ebola virus is a zoonotic pathogen that can cause severe hemorrhagic fever in humans, with up to 90% lethality. The deadly 2014 Ebola outbreak quickly made an unprecedented impact on human lives. While several vaccines and therapeutics are under development, current approaches contain several limitations, such as virus mutational escape, need for formulation or refrigeration, poor scalability, long lead-time, and high cost. To address these challenges, we developed locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) to target critical Ebola viral proteins and the human intracellular host protein Niemann-Pick C1 (NPC1), required for viral entry into infected cells...
October 2018: Nucleic Acid Therapeutics
Takeshi Kasuya, Akira Kugimiya
Gapmer antisense oligonucleotides (gapmers) sometimes cleave nontarget pre-mRNAs by recognizing target-like intronic/exonic portions. This off-target RNA cleavage could be a major cause of the hepatotoxicity that is induced by gapmers. In line with these findings, we hypothesized that gapmers with higher specificity have less hepatotoxicity, and that those with lower specificity have greater toxicity. To examine this concept, we investigated various Malat1-targeting gapmers with various computationally evaluated target specificities...
October 2018: Nucleic Acid Therapeutics
Ruchi Jain, Josh P Frederick, Eric Y Huang, Kristine E Burke, David M Mauger, Elizaveta A Andrianova, Sam J Farlow, Summar Siddiqui, Jeffrey Pimentel, Kahlin Cheung-Ong, Kristine M McKinney, Caroline Köhrer, Melissa J Moore, Tirtha Chakraborty
The advent of therapeutic mRNAs significantly increases the possibilities of protein-based biologics beyond those that can be synthesized by recombinant technologies (eg, monoclonal antibodies, extracellular enzymes, and cytokines). In addition to their application in the areas of vaccine development, immune-oncology, and protein replacement therapies, one exciting possibility is to use therapeutic mRNAs to program undesired, diseased cells to synthesize a toxic intracellular protein, causing cells to self-destruct...
October 2018: 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...
October 2018: Nucleic Acid Therapeutics
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