Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes.
Antisense oligonucleotides (ASOs) conjugated to trivalent GalNAc ligands show 10-fold enhanced potency for suppressing gene targets expressed in hepatocytes. Trivalent GalNAc is a high affinity ligand for the asialoglycoprotein receptor (ASGR)-a C-type lectin expressed almost exclusively on hepatocytes in the liver. In this communication, we show that conjugation of two and even one GalNAc sugar to single stranded chemically modified ASOs can enhance potency 5-10 fold in mice. Evaluation of the mono- and di-GalNAc ASO conjugates in an ASGR binding assay suggested that chemical features of the ASO enhance binding to the receptor and provide a rationale for the enhanced potency.
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Garth A
GA
Kinberger
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Thazha P
TP
Prakash
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Jinghua
J
Yu
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Guillermo
G
Vasquez
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Audrey
A
Low
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Alfred
A
Chappell
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Karsten
K
Schmidt
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Heather M
HM
Murray
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Hans
H
Gaus
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States.
Eric E
EE
Swayze
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, United States. Electronic address: pseth@ionisph.com.
Punit P
PP
Seth
D000116:Acetylgalactosamine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D037263:Asialoglycoprotein Receptor; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D000116:Acetylgalactosamine
ASGR; ASO; Delivery; GalNAc; Hepatocytes