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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:
    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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  2. Article ; Online: Stereochemistry Enhances Potency, Efficacy, and Durability of

    Byrne, Michael / Vathipadiekal, Vinod / Apponi, Luciano / Iwamoto, Naoki / Kandasamy, Pachamuthu / Longo, Kenneth / Liu, Fangjun / Looby, Richard / Norwood, Lauren / Shah, Anee / Shelke, Juili Dilip / Shivalila, Chikdu / Yang, Hailin / Yin, Yuan / Guo, Lankai / Bowman, Keith / Vargeese, Chandra

    Translational vision science & technology

    2021  Volume 10, Issue 1, Page(s) 23

    Abstract: Purpose: Antisense oligonucleotides have been under investigation as potential therapeutics for many diseases, including inherited retinal diseases. Chemical modifications, such as chiral phosphorothioate (PS) backbone modification, are often used to ... ...

    Abstract Purpose: Antisense oligonucleotides have been under investigation as potential therapeutics for many diseases, including inherited retinal diseases. Chemical modifications, such as chiral phosphorothioate (PS) backbone modification, are often used to improve stability and pharmacokinetic properties of these molecules. We aimed to generate a stereopure
    Methods: We generated a stereopure oligonucleotide (MALAT1-200) and assessed the potency, efficacy, and durability of its
    Results: The activity of the stereopure oligonucleotide is superior to its stereorandom mixture counterpart with the same sequence and chemical modification pattern in in vitro assays, in vivo mouse and NHP eyes, and ex vivo human retina cultures. Findings in NHPs showed durable activity of the stereopure oligonucleotide in the retina, with nearly 95% reduction of
    Conclusions: An optimized, stereopure antisense oligonucleotide shows enhanced potency, efficacy, and durability of
    Translational relevance: As novel therapeutics, stereopure oligonucleotides have the potential to enable infrequent administration and low-dose regimens for patients with genetic diseases of the eye.
    MeSH term(s) Adenocarcinoma of Lung ; Animals ; Eye ; Humans ; Lung Neoplasms ; Mice ; Oligonucleotides ; Oligonucleotides, Antisense/genetics
    Chemical Substances Oligonucleotides ; Oligonucleotides, Antisense
    Language English
    Publishing date 2021-01-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2674602-5
    ISSN 2164-2591 ; 2164-2591
    ISSN (online) 2164-2591
    ISSN 2164-2591
    DOI 10.1167/tvst.10.1.23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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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  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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    Kategorien

    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)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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