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Antisense oligonucleotide

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https://www.readbyqxmd.com/read/28641106/antisense-oligonucleotides-translation-from-mouse-models-to-human-neurodegenerative-diseases
#1
REVIEW
Kathleen M Schoch, Timothy M Miller
Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression...
June 21, 2017: Neuron
https://www.readbyqxmd.com/read/28636934/the-tmao-producing-enzyme-flavin-containing-monooxygenase-3-regulates-obesity-and-the-beiging-of-white-adipose-tissue
#2
Rebecca C Schugar, Diana M Shih, Manya Warrier, Robert N Helsley, Amy Burrows, Daniel Ferguson, Amanda L Brown, Anthony D Gromovsky, Markus Heine, Arunachal Chatterjee, Lin Li, Xinmin S Li, Zeneng Wang, Belinda Willard, YongHong Meng, Hanjun Kim, Nam Che, Calvin Pan, Richard G Lee, Rosanne M Crooke, Mark J Graham, Richard E Morton, Carl D Langefeld, Swapan K Das, Lawrence L Rudel, Nizar Zein, Arthur J McCullough, Srinivasan Dasarathy, W H Wilson Tang, Bernadette O Erokwu, Chris A Flask, Markku Laakso, Mete Civelek, Sathyamangla V Naga Prasad, Joerg Heeren, Aldons J Lusis, Stanley L Hazen, J Mark Brown
Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28636676/mitochondrion-to-endoplasmic-reticulum-apposition-length-in-zebrafish-embryo-spinal-progenitors-is-unchanged-in-response-to-perturbations-associated-with-alzheimer-s-disease
#3
Morgan Newman, Lena Halter, Anne Lim, Michael Lardelli
Mutations in the human genes PRESENILIN1 (PSEN1), PRESENILIN2 (PSEN2) and AMYLOID BETA A4 PRECURSOR PROTEIN (APP) have been identified in familial Alzheimer's disease (AD). The length of mitochondrion-endoplasmic reticulum (M-ER) appositions is increased in Psen1-/-/Psen2-/- double knockout murine embryonic fibroblasts and in fibroblasts from AD-affected individuals. Development of an easily accessible, genetically manipulable, in vivo system for studying M-ER appositions would be valuable so we attempted to manipulate M-ER apposition length in zebrafish (Danio rerio) embryos...
2017: PloS One
https://www.readbyqxmd.com/read/28635259/a-delivery-system-targeting-haemagglutinin-of-influenza-virus-a-to-facilitate-antisense-based-anti-h1n1-therapy
#4
Xiaoran Ding, Jing Yang, Dandan Lu, Qingjun Li, Zhaoyan Zhang, Zhe Zhou, Shengqi Wang
Antisense oligonucleotides (ODNs) are therapeutic molecules that hybridize to complementary target mRNA sequences. To further overcome the poor cellular uptake of ODNs, we proposed a novel strategy to deliver ODNs by conjugating the anti-influenza A virus (IAV) ODN with a peptide showing high affinity to the haemagglutinin (HA) on the surface of IAV particles or the IAV infected host cells. The HA-specific binding peptides were selected by phage display and the individual binding clones are characterized by DNA sequencing, and the selected phage was further assayed by ELISA...
June 21, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28633548/polyquaternium-mediated-delivery-of-morpholino-oligonucleotides-for-exon-skipping-in-vitro-and-in-mdx-mice
#5
Mingxing Wang, Bo Wu, Sapana N Shah, Peijuan Lu, Qilong Lu
Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that Luviquat(TM) series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28633508/rescue-of-peripheral-vestibular-function-in-usher-syndrome-mice-using-a-splice-switching-antisense-oligonucleotide
#6
Sarath Vijayakumar, Frederic F Depreux, Francine M Jodelka, Jennifer J Lentz, Frank Rigo, Timothy A Jones, Michelle L Hastings
Usher syndrome type 1C (USH1C/harmonin) is associated with profound retinal, auditory and vestibular dysfunction. We have previously reported on an antisense oligonucleotide (ASO-29) that dramatically improves auditory function and balance behavior in mice homozygous for the harmonin mutation Ush1c c.216G>A following a single systemic administration. The findings were suggestive of improved vestibular function; however, no direct vestibular assessment was made. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Usher mice...
June 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28629821/glycogen-reduction-in-myotubes-of-late-onset-pompe-disease-patients-using-antisense-technology
#7
Elisa Goina, Paolo Peruzzo, Bruno Bembi, Andrea Dardis, Emanuele Buratti
Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c...
June 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28628208/carbocyclic-c-c-bond-formation-intramolecular-radical-ring-closure-to-yield-diastereomerically-pure-7-s-me-or-7-r-me-carba-lna-nucleotide-analogs
#8
Oleksandr Plashkevych, Ram Shankar Upadhayaya, Jyoti Chattopadhyaya
In light of the impressive gene-silencing properties of carba-LNA modified oligo DNA and RNA, both in antisense RNA and siRNA approaches, which have been confirmed as proof-of-concept for biochemical applications in post-transcriptional gene silencing, we envision the true potential of carba-LNA modifications to be revealed soon. Herein we provide detailed protocols for synthesis of carba-LNA-A, -G, -(5-Me) C, and -T nucleosides on a medium/large scale (gram scale), as well as important guidelines for incorporation of these modified carba-LNAs into DNA or RNA oligonucleotides...
June 19, 2017: Current Protocols in Nucleic Acid Chemistry
https://www.readbyqxmd.com/read/28627628/phosphorothioate%C3%A2-modified-antisense-oligonucleotides-against-human-telomerase-reverse-transcriptase-sensitize-cancer-cells-to-radiotherapy
#9
Fei Cao, Xiaoping Ju, Di Chen, Lingong Jiang, Xiaofei Zhu, Shuiwang Qing, Fang Fang, Yuxin Shen, Zhen Jia, Huojun Zhang
Emergence of resistance, unavoidable systemic toxicity and unsatisfactory efficacy arethe main obstacles for traditional cancer therapy. Combination with phosphorothioate modified antisense oligonucleotides (PS‑ASODN) against human telomerase reverse transcriptase (hTERT) may enhance the therapeutic effect of irradiation. However, the effect of PS‑ASODN against hTERT on the anti‑tumor effects of irradiation in liver cancer remain unclear. In the current study, Walker 256 cells were transfected with hTERT PS‑ASODN...
June 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28624228/antisense-oligonucleotides-promote-exon-inclusion-and-correct-the-common-c-32-13t-g-gaa-splicing-variant-in-pompe-disease
#10
Erik van der Wal, Atze J Bergsma, Joon M Pijnenburg, Ans T van der Ploeg, W W M Pim Pijnappel
The most common variant causing Pompe disease is c.-32-13T>G (IVS1) in the acid α-glucosidase (GAA) gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs) to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA)-based AONs...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624227/efficient-smn-rescue-following-subcutaneous-tricyclo-dna-antisense-oligonucleotide-treatment
#11
Valérie Robin, Graziella Griffith, John-Paul L Carter, Christian J Leumann, Luis Garcia, Aurélie Goyenvalle
Spinal muscular atrophy (SMA) is a recessive disease caused by mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), whose absence dramatically affects the survival of motor neurons. In humans, the severity of the disease is lessened by the presence of a gene copy, SMN2. SMN2 differs from SMN1 by a C-to-T transition in exon 7, which modifies pre-mRNA splicing and prevents successful SMN synthesis. Splice-switching approaches using antisense oligonucleotides (AONs) have already been shown to correct this SMN2 gene transition, providing a therapeutic avenue for SMA...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624222/targeting-dmpk-with-antisense-oligonucleotide-improves-muscle-strength-in-myotonic-dystrophy-type-1-mice
#12
Dominic Jauvin, Jessina Chrétien, Sanjay K Pandey, Laurie Martineau, Lucille Revillod, Guillaume Bassez, Aline Lachon, A Robert McLeod, Geneviève Gourdon, Thurman M Wheeler, Charles A Thornton, C Frank Bennett, Jack Puymirat
Myotonic dystrophy type 1 (DM1), a dominant hereditary muscular dystrophy, is caused by an abnormal expansion of a (CTG)n trinucleotide repeat in the 3' UTR of the human dystrophia myotonica protein kinase (DMPK) gene. As a consequence, mutant transcripts containing expanded CUG repeats are retained in nuclear foci and alter the function of splicing regulatory factors members of the MBNL and CELF families, resulting in alternative splicing misregulation of specific transcripts in affected DM1 tissues. In the present study, we treated DMSXL mice systemically with a 2'-4'-constrained, ethyl-modified (ISIS 486178) antisense oligonucleotide (ASO) targeted to the 3' UTR of the DMPK gene, which led to a 70% reduction in CUG(exp) RNA abundance and foci in different skeletal muscles and a 30% reduction in the heart...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624212/light-triggerable-liposomes-for-enhanced-endolysosomal-escape-and-gene-silencing-in-pc12-cells
#13
Wenjie Chen, Wei Deng, Ewa M Goldys
Liposomes are an effective gene and/or drug delivery system, widely used in biomedical applications including gene therapy and chemotherapy. Here, we designed a photo-responsive liposome (lipVP) loaded with a photosensitizer verteporfin (VP). This photosensitizer is clinically approved for photodynamic therapy (PDT). LipVP was employed as a DNA carrier for pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor 1 (PAC1R) gene knockdown in PC12 cells. This has been done by incorporating PAC1R antisense oligonucleotides inside the lipVP cavity...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624196/evaluation-of-antisense-oligonucleotides-targeting-atxn3-in-sca3-mouse-models
#14
Lauren R Moore, Gautam Rajpal, Ian T Dillingham, Maya Qutob, Kate G Blumenstein, Danielle Gattis, Gene Hung, Holly B Kordasiewicz, Henry L Paulson, Hayley S McLoughlin
The most common dominantly inherited ataxia, spinocerebellar ataxia type 3 (SCA3), is an incurable neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene that encodes an abnormally long polyglutamine tract in the disease protein, ATXN3. Mice lacking ATXN3 are phenotypically normal; hence, disease gene suppression offers a compelling approach to slow the neurodegenerative cascade in SCA3. Here we tested antisense oligonucleotides (ASOs) that target human ATXN3 in two complementary mouse models of SCA3: yeast artificial chromosome (YAC) MJD-Q84...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624195/fluorinated-nucleotide-modifications-modulate-allele-selectivity-of-snp-targeting-antisense-oligonucleotides
#15
Michael E Østergaard, Josh Nichols, Timothy A Dwight, Walt Lima, Michael E Jung, Eric E Swayze, Punit P Seth
Antisense oligonucleotides (ASOs) have the potential to discriminate between subtle RNA mismatches such as SNPs. Certain mismatches, however, allow ASOs to bind at physiological conditions and result in RNA cleavage mediated by RNase H. We showed that replacing DNA nucleotides in the gap region of an ASO with other chemical modification can improve allele selectivity. Herein, we systematically substitute every position in the gap region of an ASO targeting huntingtin gene (HTT) with fluorinated nucleotides...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624186/gaa-deficiency-in-pompe-disease-is-alleviated-by-exon-inclusion-in-ipsc-derived-skeletal-muscle-cells
#16
Erik van der Wal, Atze J Bergsma, Tom J M van Gestel, Stijn L M In 't Groen, Holm Zaehres, Marcos J Araúzo-Bravo, Hans R Schöler, Ans T van der Ploeg, W W M Pim Pijnappel
Pompe disease is a metabolic myopathy caused by deficiency of the acid α-glucosidase (GAA) enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1) GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs) that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28623256/lna-dna-mixmer-based-antisense-oligonucleotides-correct-alternative-splicing-of-the%C3%A2-smn2-gene-and-restore-smn-protein-expression-in-type-1-sma-fibroblasts
#17
Aleksander Touznik, Rika Maruyama, Kana Hosoki, Yusuke Echigoya, Toshifumi Yokota
Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting motor neurons, and is currently the most frequent genetic cause of infant mortality. SMA is caused by a loss-of-function mutation in the survival motor neuron 1 (SMN1) gene. SMN2 is an SMN1 paralogue, but cannot compensate for the loss of SMN1 since exon 7 in SMN2 mRNA is excluded (spliced out) due to a single C-to-T nucleotide transition in the exon 7. One of the most promising strategies to treat SMA is antisense oligonucleotide (AON)-mediated therapy...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28621426/foxd1-protein-interacts-with-wnt-and-bmp-signaling-to-differentially-pattern-mesoderm-and-neural-tissue
#18
Hanna Polevoy, Anastasia Malyarova, Yuri Fonar, Sara Elias, Dale Frank
The foxd1 gene (previously known as Brain Factor 2/BF2) is expressed during early Xenopus laevis development. At gastrula stages, foxd1 is expressed in dorsal mesoderm regions fated for muscle and notochord, while at neurula stages, foxd1 is expressed in the forebrain region. Previous studies in the neural plate showed that FoxD1 protein acts as transcriptional repressor downstream of BMP antagonism, neuralizing the embryo to control anterior neural cell fates. FoxD1 mesoderm function was not rigorously analyzed, but ectopic FoxD1 levels increased muscle marker expression in embryos...
2017: International Journal of Developmental Biology
https://www.readbyqxmd.com/read/28617055/new-treatment-strategies-for-ulcerative-colitis
#19
Julian Panés, Ignacio Alfaro
Therapeutic strategies in ulcerative colitis are evolving. A personalized and optimal use of available drugs and the integration of new drug classes are the cornerstones underpinning the new treatment paradigms. Areas covered: A structured literature search in Medline and PubMed, Cochrane meta-analyses, and abstracts of international congresses has been performed to review therapeutic approaches to ulcerative colitis. The primary therapeutic objective of therapy is to achieve clinical remission since persistence of active disease, even if mild, leads to a significant reduction in quality of life...
June 21, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28615361/targeting-kras-dependent-tumors-with-azd4785-a-high-affinity-therapeutic-antisense-oligonucleotide-inhibitor-of-kras
#20
Sarah J Ross, Alexey S Revenko, Lyndsey L Hanson, Rebecca Ellston, Anna Staniszewska, Nicky Whalley, Sanjay K Pandey, Mitchell Revill, Claire Rooney, Linda K Buckett, Stephanie K Klein, Kevin Hudson, Brett P Monia, Michael Zinda, David C Blakey, Paul D Lyne, A Robert Macleod
Activating mutations in KRAS underlie the pathogenesis of up to 20% of human tumors, and KRAS is one of the most frequently mutated genes in cancer. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. We describe the preclinical evaluation of AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting KRAS mRNA. AZD4785 potently and selectively depleted cellular KRAS mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in KRAS mutant cells...
June 14, 2017: Science Translational Medicine
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