Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS

• Autores: Pachamuthu Kandasamy, Yuanjing Liu, Vincent Aduda, Sandheep Akare, Rowshon Alam, Amy Andreucci, David Boulay, Keith Bowman, Michael Byrne, Megan Cannon, Onanong Chivatakarn, Juili Dilip Shelke, Naoki Iwamoto, Tomomi Kawamoto, Jayakanthan Kumarasamy, Sarah Lamore, Muriel Lemaitre, Xuena Lin, Kenneth A. Longo, Richard Looby, Subramanian Marappan, Jake Metterville, Susovan Mohapatra, Bridget Newman, Ik-Hyeon Paik, Saurabh Patil, Erin Purcell-Estabrook, Mamoru Shimizu, Pochi Shum, Stephany Standley, Kris Taborn, Snehlata Tripathi, Hailin Yang, Yuan Yin, Xiansi Zhao, Elena Dale, Chandra Vargeese
• Localización: Nucleic acids research, ISSN 0305-1048, Vol. 50, Nº. 10, 2022, págs. 5401-5423
• Idioma: inglés
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• Resumen

  • 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.