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  1. Article ; Online: Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference.

    Liu, Wei / Iwamoto, Naoki / Marappan, Subramanian / Luu, Khoa / Tripathi, Snehlata / Purcell-Estabrook, Erin / Shelke, Juili Dilip / Shah, Himali / Lamattina, Anthony / Pan, Qianli / Schrand, Brett / Favaloro, Frank / Bedekar, Mugdha / Chatterjee, Arindom / Desai, Jigar / Kawamoto, Tomomi / Lu, Genliang / Metterville, Jake / Samaraweera, Milinda /
    Prakasha, Priyanka Shiva / Yang, Hailin / Yin, Yuan / Yu, Hui / Giangrande, Paloma H / Byrne, Michael / Kandasamy, Pachamuthu / Vargeese, Chandra

    Nucleic acids research

    2023  Volume 51, Issue 9, Page(s) 4126–4147

    Abstract: Herein, we report the systematic investigation of stereopure phosphorothioate (PS) and phosphoryl guanidine (PN) linkages on siRNA-mediated silencing. The incorporation of appropriately positioned and configured stereopure PS and PN linkages to N- ... ...

    Abstract Herein, we report the systematic investigation of stereopure phosphorothioate (PS) and phosphoryl guanidine (PN) linkages on siRNA-mediated silencing. The incorporation of appropriately positioned and configured stereopure PS and PN linkages to N-acetylgalactosamine (GalNAc)-conjugated siRNAs based on multiple targets (Ttr and HSD17B13) increased potency and durability of mRNA silencing in mouse hepatocytes in vivo compared with reference molecules based on clinically proven formats. The observation that the same modification pattern had beneficial effects on unrelated transcripts suggests that it may be generalizable. The effect of stereopure PN modification on silencing is modulated by 2'-ribose modifications in the vicinity, particularly on the nucleoside 3' to the linkage. These benefits corresponded with both an increase in thermal instability at the 5'-end of the antisense strand and improved Argonaute 2 (Ago2) loading. Application of one of our most effective designs to generate a GalNAc-siRNA targeting human HSD17B13 led to ∼80% silencing that persisted for at least 14 weeks after administration of a single 3 mg/kg subcutaneous dose in transgenic mice. The judicious use of stereopure PN linkages improved the silencing profile of GalNAc-siRNAs without disrupting endogenous RNA interference pathways and without elevating serum biomarkers for liver dysfunction, suggesting they may be suitable for therapeutic application.
    MeSH term(s) Animals ; Humans ; Mice ; Gene Silencing ; Mice, Transgenic ; RNA Interference ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics
    Chemical Substances RNA, Messenger ; RNA, Small Interfering
    Language English
    Publishing date 2023-04-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad268
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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  2. Article ; Online: Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS.

    Kandasamy, Pachamuthu / Liu, Yuanjing / Aduda, Vincent / Akare, Sandheep / Alam, Rowshon / Andreucci, Amy / Boulay, David / Bowman, Keith / Byrne, Michael / Cannon, Megan / Chivatakarn, Onanong / Shelke, Juili Dilip / Iwamoto, Naoki / Kawamoto, Tomomi / Kumarasamy, Jayakanthan / Lamore, Sarah / Lemaitre, Muriel / Lin, Xuena / Longo, Kenneth /
    Looby, Richard / Marappan, Subramanian / Metterville, Jake / Mohapatra, Susovan / Newman, Bridget / Paik, Ik-Hyeon / Patil, Saurabh / Purcell-Estabrook, Erin / Shimizu, Mamoru / Shum, Pochi / Standley, Stephany / Taborn, Kris / Tripathi, Snehlata / Yang, Hailin / Yin, Yuan / Zhao, Xiansi / Dale, Elena / Vargeese, Chandra

    Nucleic acids research

    2022  Volume 50, Issue 10, Page(s) 5401–5423

    Abstract: Attaining sufficient tissue exposure at the site of action to achieve the desired pharmacodynamic effect on a target is an important determinant for any drug discovery program, and this can be particularly challenging for oligonucleotides in deep tissues ...

    Abstract Attaining sufficient tissue exposure at the site of action to achieve the desired pharmacodynamic effect on a target is an important determinant for any drug discovery program, and this can be particularly challenging for oligonucleotides in deep tissues of the CNS. Herein, we report the synthesis and impact of stereopure phosphoryl guanidine-containing backbone linkages (PN linkages) to oligonucleotides acting through an RNase H-mediated mechanism, using Malat1 and C9orf72 as benchmarks. We found that the incorporation of various types of PN linkages to a stereopure oligonucleotide backbone can increase potency of silencing in cultured neurons under free-uptake conditions 10-fold compared with similarly modified stereopure phosphorothioate (PS) and phosphodiester (PO)-based molecules. One of these backbone types, called PN-1, also yielded profound silencing benefits throughout the mouse brain and spinal cord at low doses, improving both the potency and durability of response, especially in difficult to reach brain tissues. Given these benefits in preclinical models, the incorporation of PN linkages into stereopure oligonucleotides with chimeric backbone modifications has the potential to render regions of the brain beyond the spinal cord more accessible to oligonucleotides and, consequently, may also expand the scope of neurological indications amenable to oligonucleotide therapeutics.
    MeSH term(s) Animals ; Cells, Cultured ; Central Nervous System ; Guanidine/chemistry ; Mice ; Neurons/drug effects ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/pharmacology ; Phosphorothioate Oligonucleotides ; Ribonuclease H/metabolism
    Chemical Substances Oligonucleotides, Antisense ; Phosphorothioate Oligonucleotides ; Ribonuclease H (EC 3.1.26.4) ; Guanidine (JU58VJ6Y3B)
    Language English
    Publishing date 2022-01-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkac037
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Endogenous ADAR-mediated RNA editing in non-human primates using stereopure chemically modified oligonucleotides.

    Monian, Prashant / Shivalila, Chikdu / Lu, Genliang / Shimizu, Mamoru / Boulay, David / Bussow, Karley / Byrne, Michael / Bezigian, Adam / Chatterjee, Arindom / Chew, David / Desai, Jigar / Favaloro, Frank / Godfrey, Jack / Hoss, Andrew / Iwamoto, Naoki / Kawamoto, Tomomi / Kumarasamy, Jayakanthan / Lamattina, Anthony / Lindsey, Amber /
    Liu, Fangjun / Looby, Richard / Marappan, Subramanian / Metterville, Jake / Murphy, Ronelle / Rossi, Jeff / Pu, Tom / Bhattarai, Bijay / Standley, Stephany / Tripathi, Snehlata / Yang, Hailin / Yin, Yuan / Yu, Hui / Zhou, Cong / Apponi, Luciano H / Kandasamy, Pachamuthu / Vargeese, Chandra

    Nature biotechnology

    2022  Volume 40, Issue 7, Page(s) 1093–1102

    Abstract: Technologies that recruit and direct the activity of endogenous RNA-editing enzymes to specific cellular RNAs have therapeutic potential, but translating them from cell culture into animal models has been challenging. Here we describe short, chemically ... ...

    Abstract Technologies that recruit and direct the activity of endogenous RNA-editing enzymes to specific cellular RNAs have therapeutic potential, but translating them from cell culture into animal models has been challenging. Here we describe short, chemically modified oligonucleotides called AIMers that direct efficient and specific A-to-I editing of endogenous transcripts by endogenous adenosine deaminases acting on RNA (ADAR) enzymes, including the ubiquitously and constitutively expressed ADAR1 p110 isoform. We show that fully chemically modified AIMers with chimeric backbones containing stereopure phosphorothioate and nitrogen-containing linkages based on phosphoryl guanidine enhanced potency and editing efficiency 100-fold compared with those with uniformly phosphorothioate-modified backbones in vitro. In vivo, AIMers targeted to hepatocytes with N-acetylgalactosamine achieve up to 50% editing with no bystander editing of the endogenous ACTB transcript in non-human primate liver, with editing persisting for at least one month. These results support further investigation of the therapeutic potential of stereopure AIMers.
    MeSH term(s) Animals ; Oligonucleotides ; Primates/genetics ; Primates/metabolism ; RNA ; RNA Editing/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
    Chemical Substances Oligonucleotides ; RNA-Binding Proteins ; RNA (63231-63-0)
    Language English
    Publishing date 2022-03-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-022-01225-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2167: Show issues Location:
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    Zs.MO 137: Show issues
    Zs.MG 43: Show issues

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  4. Article ; Online: Control of backbone chemistry and chirality boost oligonucleotide splice switching activity.

    Kandasamy, Pachamuthu / McClorey, Graham / Shimizu, Mamoru / Kothari, Nayantara / Alam, Rowshon / Iwamoto, Naoki / Kumarasamy, Jayakanthan / Bommineni, Gopal R / Bezigian, Adam / Chivatakarn, Onanong / Butler, David C D / Byrne, Michael / Chwalenia, Katarzyna / Davies, Kay E / Desai, Jigar / Shelke, Juili Dilip / Durbin, Ann F / Ellerington, Ruth / Edwards, Ben /
    Godfrey, Jack / Hoss, Andrew / Liu, Fangjun / Longo, Kenneth / Lu, Genliang / Marappan, Subramanian / Oieni, Jacopo / Paik, Ik-Hyeon / Estabrook, Erin Purcell / Shivalila, Chikdu / Tischbein, Maeve / Kawamoto, Tomomi / Rinaldi, Carlo / Rajão-Saraiva, Joana / Tripathi, Snehlata / Yang, Hailin / Yin, Yuan / Zhao, Xiansi / Zhou, Cong / Zhang, Jason / Apponi, Luciano / Wood, Matthew J A / Vargeese, Chandra

    Nucleic acids research

    2022  Volume 50, Issue 10, Page(s) 5443–5466

    Abstract: Although recent regulatory approval of splice-switching oligonucleotides (SSOs) for the treatment of neuromuscular disease such as Duchenne muscular dystrophy has been an advance for the splice-switching field, current SSO chemistries have shown limited ... ...

    Abstract Although recent regulatory approval of splice-switching oligonucleotides (SSOs) for the treatment of neuromuscular disease such as Duchenne muscular dystrophy has been an advance for the splice-switching field, current SSO chemistries have shown limited clinical benefit due to poor pharmacology. To overcome limitations of existing technologies, we engineered chimeric stereopure oligonucleotides with phosphorothioate (PS) and phosphoryl guanidine-containing (PN) backbones. We demonstrate that these chimeric stereopure oligonucleotides have markedly improved pharmacology and efficacy compared with PS-modified oligonucleotides, preventing premature death and improving median survival from 49 days to at least 280 days in a dystrophic mouse model with an aggressive phenotype. These data demonstrate that chemical optimization alone can profoundly impact oligonucleotide pharmacology and highlight the potential for continued innovation around the oligonucleotide backbone. More specifically, we conclude that chimeric stereopure oligonucleotides are a promising splice-switching modality with potential for the treatment of neuromuscular and other genetic diseases impacting difficult to reach tissues such as the skeletal muscle and heart.
    MeSH term(s) Animals ; Exons ; Mice ; Muscle, Skeletal ; Muscular Dystrophy, Duchenne/drug therapy ; Muscular Dystrophy, Duchenne/therapy ; Oligonucleotides, Antisense/chemistry ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/pharmacology ; Phosphorothioate Oligonucleotides/chemistry ; Phosphorothioate Oligonucleotides/pharmacology ; RNA Splicing/drug effects
    Chemical Substances Oligonucleotides, Antisense ; Phosphorothioate Oligonucleotides
    Language English
    Publishing date 2022-01-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkac018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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