Preclinical PK and PD studies on 2'-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model.
Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2'-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (approximately 46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols.
Heemskerk
Hans
H
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
de Winter
Christa
C
van Kuik
Petra
P
Heuvelmans
Niki
N
Sabatelli
Patrizia
P
Rimessi
Paola
P
Braghetta
Paola
P
van Ommen
Gert-Jan B
GJ
de Kimpe
Sjef
S
Ferlini
Alessandra
A
Aartsma-Rus
Annemieke
A
van Deutekom
Judith C T
JC
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D016189:Dystrophin / Q000008:administration & dosage; D005455:Fluorescent Antibody Technique; D051379:Mice; D018101:Mice, Inbred mdx; D054735:Phosphorothioate Oligonucleotides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016372:RNA, Antisense / Q000493:pharmacokinetics / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016189:Dystrophin; D054735:Phosphorothioate Oligonucleotides; D016372:RNA, Antisense
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