An oral antisense oligonucleotide for PCSK9 inhibition.

Animals Dogs Macaca fascicularis Oligonucleotides, Antisense PCSK9 Inhibitors Rats Serine Endopeptidases

Journal

Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086

Informations de publication

Date de publication:
12 05 2021
Historique:
received: 09 10 2020
accepted: 23 04 2021
entrez: 13 5 2021
pubmed: 14 5 2021
medline: 13 7 2021
Statut: ppublish

Résumé

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by

Identifiants

DOI: 10.1126/scitranslmed.abe9117 PMID: 33980578
pubmed: 33980578
pii: 13/593/eabe9117
doi: 10.1126/scitranslmed.abe9117
pii:
doi:

Substances chimiques

Oligonucleotides, Antisense 0
PCSK9 Inhibitors 0
PCSK9 protein, rat EC 3.4.21.-
Serine Endopeptidases EC 3.4.21.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Auteurs

Peter Gennemark (P)

Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden. peter.gennemark@astrazeneca.com.
Department of Biomedical Engineering, Linköping University, SE-581 83 Linköping, Sweden.
ORCID: 0000-0002-7865-7454

Katrin Walter (K)

Inhalation Product Development, Pharmaceutical Technology and Development, Operations, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0001-9147-9472

Niclas Clemmensen (N)

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Dinko Rekić (D)

Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Catarina A M Nilsson (CAM)

Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-8096-4226

Jane Knöchel (J)

Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Mikko Hölttä (M)

Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0001-6024-3686

Linda Wernevik (L)

Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-9829-3037

Birgitta Rosengren (B)

Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Dorota Kakol-Palm (D)

Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Yanfeng Wang (Y)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.

Rosie Z Yu (RZ)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
ORCID: 0000-0001-9266-7280

Richard S Geary (RS)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
ORCID: 0000-0002-6308-3179

Stan J Riney (SJ)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
ORCID: 0000-0001-9049-8639

Brett P Monia (BP)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
ORCID: 0000-0002-7473-1012

Rikard Isaksson (R)

Early Biometrics and Statistical Innovation, Data Science and Artificial Intelligence, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Rasmus Jansson-Löfmark (R)

Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0003-1773-197X

Cristina S J Rocha (CSJ)

Functional and Mechanistic Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-6008-9532

Daniel Lindén (D)

Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0003-4158-8018

Eva Hurt-Camejo (E)

Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-1704-6879

Rosanne Crooke (R)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.

Lloyd Tillman (L)

Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
ORCID: 0000-0002-0603-3829

Tina Rydén-Bergsten (T)

Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-0666-4700

Björn Carlsson (B)

Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-3023-9878

Ulf Andersson (U)

CVRM Safety, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Marie Elebring (M)

Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0003-2073-0986

Anna Tivesten (A)

CVRM CMC Projects, Pharmaceutical Sciences, R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Nigel Davies (N)

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.
ORCID: 0000-0002-0679-3377

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › An oral antisense oligonucleotide for PCSK9 inhibition.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Carnivora › Pinnipedia › Canidae › Chiens › An oral antisense oligonucleotide for PCSK9 inhibition.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Cercopithecidae › Cercopithecinae › Macaca › Macaca fascicularis › An oral antisense oligonucleotide for PCSK9 inhibition.
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Sondes moléculaires › Sondes d'acide nucléique › Éléments antisens (génétique) › Oligonucléotides antisens › An oral antisense oligonucleotide for PCSK9 inhibition.
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents régulateurs du métabolisme des lipides › Hypolipémiants › Anticholestérolémiants › Inhibiteurs de PCSK9 › An oral antisense oligonucleotide for PCSK9 inhibition.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › An oral antisense oligonucleotide for PCSK9 inhibition.
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Protéases à sérine › Serine endopeptidases › An oral antisense oligonucleotide for PCSK9 inhibition.