Glucagon Like Peptide 1 Receptor Agonists for Targeted Delivery of Antisense Oligonucleotides to Pancreatic Beta Cell

  • J Am Chem Soc. 2021 Mar 10;143(9):3416-3429. doi: 10.1021/jacs.0c12043.
Laurent Knerr  1 ,  Thazha P Prakash  2 ,  Richard Lee  2 ,  William J Drury Iii  1 ,  Mehran Nikan  2 ,  Wuxia Fu  2 ,  Elaine Pirie  2 ,  Leonardo De Maria  3 ,  Eric Valeur  1 ,  Ahlke Hayen  1 ,  Maria Ölwegård-Halvarsson  1 ,  Johan Broddefalk  1 ,  Carina Ämmälä  4 ,  Michael E Østergaard  2 ,  Johan Meuller  5 ,  Linda Sundström  5 ,  Patrik Andersson  6 ,  David Janzén  7 ,  Rasmus Jansson-Löfmark  7 ,  Punit P Seth  2 ,  Shalini Andersson  8
Affiliations
  • 1. Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 2. Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, California 92010, United States.
  • 3. Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 4. Bioscience, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 5. Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 6. Respiratory and Immunology Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 7. DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 8. Research and early Development, Discovery Sciences,, AstraZeneca, Gothenburg, Sweden.
PMID: 33626278 DOI: 10.1021/jacs.0c12043
Abstract

The extra hepatic delivery of Antisense Oligonucleotides (ASOs) remains a challenge and hampers the widespread application of this powerful class of therapeutic agents. In that regard, pancreatic beta cells are a particularly attractive but challenging cell type because of their pivotal role in diabetes and the fact that they are refractory to uptake of unconjugated ASOs. To circumvent this, we have expanded our understanding of the structure activity relationship of ASOs conjugated to Glucagon Like Peptide 1 Receptor (GLP1R) agonist peptide ligands. We demonstrate the key role of the linker chemistry and its optimization to design maleimide based conjugates with improved in vivo efficacy. In addition, truncation studies and scoping of a diverse set of GLP1R agonists proved fruitful to identify additional targeting ligands efficacious in vivo including native hGLP1(7-36)NH2. Variation of the carrier peptide also shed some light on the dramatic impact of subtle sequence differences on the corresponding ASO conjugate performance in vivo, an area which clearly warrant further investigations. We have confirmed the remarkable potential of GLP1R agonist conjugation for the delivery of ASOs to pancreatic beta cell by effectively knocking down islet amyloid polypeptide (IAPP) mRNA, a potential proapoptotic target, in mice.

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