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Nucleic Acid Therapeutics

Liande Li, Xiulong Shen, Zhongtian Liu, Michaela Norrbom, Thazha P Prakash, Daniel O'Reilly, Vivek K Sharma, Masad J Damha, Jonathan K Watts, Frank Rigo, David R Corey
Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA...
January 17, 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...
December 1, 2017: Nucleic Acid Therapeutics
Yanghee Kim, Young Gyu Kang, Jeong Yong Choe, Dooyoung Lee, Chanseok Shin, Sun Woo Hong, Dong-Ki Lee
Specific gene silencing through RNA interference (RNAi) holds great promise as the next-generation therapeutic development platform. Previously, we have shown that branched, tripodal interfering RNA (tiRNA) structures could simultaneously trigger RNAi-mediated gene silencing of three target genes with 38 nt-long guide strands associated with Argonaute 2. Herein, we show that the branched RNA structure can trigger effective gene silencing in Dicer knockout cell line, demonstrating that the Dicer-mediated processing is not required for tiRNA activity...
December 1, 2017: Nucleic Acid Therapeutics
Stanley T Crooke, Brenda F Baker, Nguyen C Pham, Steven G Hughes, T Jesse Kwoh, Danlin Cai, Sotirios Tsimikas, Richard S Geary, Sanjay Bhanot
Systemically administered 2'-O-methoxyethyl (2'MOE) antisense oligonucleotides (ASOs) accumulate in the kidney and metabolites are cleared in urine. The effects of eleven 2'MOE ASOs on renal function were assessed in 2,435 patients from 32 phase 2 and phase 3 trials. The principle analysis was on data from 28 randomized placebo-controlled trials. Mean levels of renal parameters remained within normal ranges over time across dose groups. Patient-level meta-analyses demonstrated a significant difference between placebo-treated and 2'MOE ASO-treated patients at doses >175 mg/week in the percentage and absolute change from baseline for serum creatinine and estimated glomerular filtration rate...
November 29, 2017: Nucleic Acid Therapeutics
Shruti Sasaki, Shuling Guo
Nucleic acid therapeutics are an established class of drugs that enable specific targeting of a gene of interest. This diverse family of drugs includes antisense oligonucleotides, siRNAs, and mRNA replacement therapies, which can elicit both gene repression and activation, primarily at the RNA level. Recent advances in medicinal chemistry have increased drug potency and enhanced delivery and distribution to a broad array of tissue and cell types. A key advantage of nucleic acid therapeutics is in their application to monogenic diseases...
November 21, 2017: Nucleic Acid Therapeutics
Daniel Capaldi, Andy Teasdale, Scott Henry, Nadim Akhtar, Cathaline den Besten, Samantha Gao-Sheridan, Matthias Kretschmer, Neal Sharpe, Ben Andrews, Brigitte Burm, Jeffrey Foy
This white paper, which is the 10th in a series intended to address issues associated with the development of therapeutic oligonucleotides, examines the subject of product-related impurities. The authors consider chemistry and safety aspects and advance arguments in favor of platform approaches to impurity identification and qualification. Reporting, identification, and qualification thresholds suitable for product-related impurities of therapeutic oligonucleotides are proposed.
November 10, 2017: Nucleic Acid Therapeutics
Shirley H Purvis, Jeffrey R Keefer, Yolanda M Fortenberry, Emily A Barron-Casella, James F Casella
The pathophysiology of sickle cell disease (SCD) is dependent on the polymerization of deoxygenated sickle hemoglobin (HbS), leading to erythrocyte deformation (sickling) and vaso-occlusion within the microvasculature. Following deoxygenation, there is a delay time before polymerization is initiated, during which nucleation of HbS monomers occurs. An agent with the ability to extend this delay time or slow polymerization would therefore hold a therapeutic, possibly curative, potential. We used the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method to screen for HbS-binding RNA aptamers modified with nuclease-resistant 2'-fluoropyrimidines...
October 17, 2017: Nucleic Acid Therapeutics
Bruno M D C Godinho, James W Gilbert, Reka A Haraszti, Andrew H Coles, Annabelle Biscans, Loic Roux, Mehran Nikan, Dimas Echeverria, Matthew Hassler, Anastasia Khvorova
Therapeutic oligonucleotides, such as small interfering RNAs (siRNAs), hold great promise for the treatment of incurable genetically defined disorders by targeting cognate toxic gene products for degradation. To achieve meaningful tissue distribution and efficacy in vivo, siRNAs must be conjugated or formulated. Clear understanding of the pharmacokinetic (PK)/pharmacodynamic behavior of these compounds is necessary to optimize and characterize the performance of therapeutic oligonucleotides in vivo. In this study, we describe a simple and reproducible methodology for the evaluation of in vivo blood/plasma PK profiles and tissue distribution of oligonucleotides...
October 12, 2017: Nucleic Acid Therapeutics
Nobuhiko Sugito, Kohei Taniguchi, Yuki Kuranaga, Maki Ohishi, Tomoyoshi Soga, Yuko Ito, Mitsuru Miyachi, Ken Kikuchi, Hajime Hosoi, Yukihiro Akao
Rhabdomyosarcoma (RMS) is a soft tissue sarcoma and is most frequently found in children. In RMS, there are two major subtypes, that is, embryonal RMS and alveolar RMS (ARMS). ARMS has exclusively the worse prognosis and is caused by formation of the chimeric PAX3-FOXO1 gene. Regarding cancer, the Warburg effect is known as a feature of cancer-specific metabolism. Polypyrimidine tract-binding protein 1 (PTBP1), a splicer of pyruvate kinase muscle (PKM) mRNA, is a positive regulator of cancer-specific energy metabolism...
October 5, 2017: Nucleic Acid Therapeutics
Jonathan C Hagopian, Alexander S Hamil, Arjen van den Berg, Bryan R Meade, Akiko Eguchi, Caroline Palm-Apergi, Steven F Dowdy
Small double-stranded, left-handed hairpin (LHP) RNAs containing a 5'-guide-loop-passenger-3' structure induce RNAi responses by a poorly understood mechanism. To explore LHPs, we synthesized fully 2'-modified LHP RNAs targeting multiple genes and found all to induce robust RNAi responses. Deletion of the loop and nucleotides at the 5'-end of the equivalent passenger strand resulted in a smaller LHP that still induced strong RNAi responses. Surprisingly, progressive deletion of up to 10 nucleotides from the 3'-end of the guide strand resulted in a 32mer LHP capable of inducing robust RNAi responses...
October 2017: Nucleic Acid Therapeutics
Jumpei Ariyoshi, Yohei Matsuyama, Akio Kobori, Akira Murakami, Hiroshi Sugiyama, Asako Yamayoshi
MicroRNAs (miRNAs) regulate gene expression by forming RNA-induced silencing complexes (RISCs) and have been considered as promising therapeutic targets. MiRNA is an essential component of RISC for the modulation of gene expression. Therefore, the release of miRNA from RISC is considered as an effective method for the inhibition of miRNA functions. In our previous study, we reported that anti-miRNA oligonucleotides (AMOs), which are composed of the 2'-O-methyl (2'-OMe) RNA, could induce the release of miRNA from RISC...
October 2017: Nucleic Acid Therapeutics
Rosie Z Yu, Rudy Gunawan, Richard S Geary, Steven G Hughes, Scott P Henry, Yanfeng Wang
The potential of QT prolongation of ten 2'-O-methoxyethyl-modified (2'-MOE) antisense oligonucleotides (ASOs) was evaluated retrospectively via exposure/response (ER) analysis using data from Phase 1 clinical studies in healthy subjects. All Phase 1 studies were double-blind, placebo-controlled, single and multiple ascending dose studies designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the ASOs in healthy subjects. The active doses in these studies ranged from 50 to 450 mg administered by subcutaneous (SC) injection in single and multiple ascending dose cohorts...
October 2017: Nucleic Acid Therapeutics
Annemieke Aartsma-Rus, Volker Straub, Robert Hemmings, Manuel Haas, Gabriele Schlosser-Weber, Violeta Stoyanova-Beninska, Eugenio Mercuri, Francesco Muntoni, Bruno Sepodes, Elizabeth Vroom, Pavel Balabanov
Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD...
October 2017: Nucleic Acid Therapeutics
Egon Urgard, Aleksei Brjalin, Ülo Langel, Margus Pooga, Ana Rebane, Tarmo Annilo
The microRNA (miRNA) microRNA-34a (miR-34a) regulates a number of genes involved in cell cycle control and is therefore considered to have a high therapeutic potential. MiR-34a expression is often downregulated in cancer cells and its restoration has been shown to exert a tumor-suppressive effect. However, effective and safe delivery of synthetic miRNA analogs into cancer cells remains a challenge. The aim of this study was to evaluate cell-penetrating peptide PepFect (PF)14 as a carrier for delivery of miR-34a-5p into human primary prostate carcinoma-1 (PPC-1) cells...
October 2017: Nucleic Acid Therapeutics
Suzanne Paz, Jill Hsiao, Patrick Cauntay, Armand Soriano, Lawrence Bai, Todd Machemer, Xiaokun Xiao, Shuling Guo, Gene Hung, Husam Younis, C Frank Bennett, Scott Henry, Theodore J Yun, Sébastien Burel
Antisense oligonucleotides (ASOs) are widely accepted therapeutic agents that suppress RNA transcription. While the majority of ASOs are well tolerated in vivo, few sequences trigger inflammatory responses in absence of conventional CpG motifs. In this study, we identified non-CpG oligodeoxy-nucleotide (ODN) capable of triggering an inflammatory response resulting in B cell and macrophage activation in a MyD88- and TLR9-dependent manner. In addition, we found the receptor for advance glycation end product (RAGE) receptor to be involved in the initiation of inflammatory response to suboptimal concentrations of both CpG- and non-CpG-containing ODNs...
October 2017: Nucleic Acid Therapeutics
Shashi Gupta, Daniel W Drolet, Steven K Wolk, Sheela M Waugh, John C Rohloff, Jeffery D Carter, Wesley S Mayfield, Matthew R Otis, Catherine R Fowler, Tomoki Suzuki, Masao Hirota, Yuichi Ishikawa, Daniel J Schneider, Nebojsa Janjic
The addition of novel side chains at the 5-position of uracil is an effective means to increase chemical diversity of aptamers and hence the success rate for discovery of high-affinity ligands to protein targets. Such modifications also increase nuclease resistance, which is useful in a range of applications, especially for therapeutics. In this study, we assess the impact of these side chains on plasma pharmacokinetics of modified aptamers conjugated to a 40 kDa polyethylene glycol. We show that clearance from plasma depends on relative hydrophobicity: side chains with a negative cLogP (more hydrophilic) result in slower plasma clearance compared with side chains with a positive cLogP (more hydrophobic)...
September 29, 2017: Nucleic Acid Therapeutics
Christina Kratschmer, Matthew Levy
There is increasing interest in the use of aptamers for the development of therapeutics. However, as oligonucleotides, aptamers are susceptible to nuclease degradation; poor serum stability is likely to negatively affect in vivo function. Modified nucleotides have been used to thwart nuclease degradation. However, few studies report the serum stability of selected aptamers. In this study, we examined the effect of various chemical modifications (2'-deoxy, 2'-hydroxyl, 2'-fluoro, and 2'-O-methyl) on the stability of a control oligonucleotide sequence following incubation in frozen human, fresh mouse, and fresh human serum...
September 25, 2017: Nucleic Acid Therapeutics
Jennifer L Marlowe, Violetta Akopian, Priya Karmali, Douglas Kornbrust, Jennifer Lockridge, Sean Semple
The use of lipid formulations has greatly improved the ability to effectively deliver oligonucleotides and has been instrumental in the rapid expansion of therapeutic development programs using oligonucleotide drugs. However, the development of such complex multicomponent therapeutics requires the implementation of unique, scientifically sound approaches to the nonclinical development of these drugs, based upon a hybrid of knowledge and experiences drawn from small molecule, protein, and oligonucleotide therapeutic drug development...
August 2017: Nucleic Acid Therapeutics
Scott P Henry, Padmakumar Narayanan, Lijiang Shen, Sanjay Bhanot, Husam S Younis, Sebastien A Burel
Decreases in platelet (PLT) counts observed in nonhuman primates (NHPs) given 2'-O-methoxyethyl modified antisense inhibitors (2'-MOE ASOs) have been reported, but the incidence and severity of the change vary considerably between sequences, studies, and animals. This article will broadly illustrate the spectrum of effects on PLT count in NHPs. From queries of an NHP safety database representing over 102 independent 2'-MOE ASOs, from 61 studies and >2200 NHPs, two patterns of PLT changes emerged. The first is a consistent and reproducible decrease in group mean values, observed with about 30% of the compounds, in which PLT count typically remains ≥150K cells/μL...
August 2017: Nucleic Acid Therapeutics
Aaron J Donner, Edward V Wancewicz, Heather M Murray, Sarah Greenlee, Noah Post, Melanie Bell, Walt F Lima, Eric E Swayze, Punit P Seth
Phosphorothioate (PS) modified antisense oligonucleotides (ASOs) have progressed rapidly in the clinic for treating a variety of disease indications. We previously demonstrated that the activity of PS ASOs in the liver can be enhanced by co-infusion of an excipient oligonucleotide (EON). It was posited that the EON saturates a nonproductive uptake pathway(s) thereby permitting accumulation of the PS ASO in a productive tissue compartment. In this report, we measured PS ASO activity following administration by bolus, infusion or co-fusion with EON within hepatocytes and nonparenchymal cells (NPCs), of the liver...
August 2017: Nucleic Acid Therapeutics
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