Preclinical PK and PD studies on 2′-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model

Hans Heemskerk, Christa De Winter, Petra Van Kuik, Niki Heuvelmans, Patrizia Sabatelli, Paola Rimessi, Paola Braghetta, Gert Jan B Van Ommen, Sjef De Kimpe, Alessandra Ferlini, Annemieke Aartsma-Rus, Judith Ct Van Deutekom

Research output: Contribution to journalArticle

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Abstract

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 (∼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.

Original languageEnglish
Pages (from-to)1210-1217
Number of pages8
JournalMolecular Therapy
Volume18
Issue number6
DOIs
Publication statusPublished - Jun 2010

Fingerprint

Inbred mdx Mouse
Antisense Oligonucleotides
Oligonucleotides
Pharmacokinetics
RNA
Dystrophin
Exons
Muscles
Half-Life
Dog Diseases
Duchenne Muscular Dystrophy
Subcutaneous Injections
Clinical Protocols
Intraperitoneal Injections
Intravenous Administration
Muscle Cells
Biological Availability
Smooth Muscle
Myocardium
Cell Culture Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology
  • Medicine(all)

Cite this

Heemskerk, H., De Winter, C., Van Kuik, P., Heuvelmans, N., Sabatelli, P., Rimessi, P., ... Van Deutekom, J. C. (2010). Preclinical PK and PD studies on 2′-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. Molecular Therapy, 18(6), 1210-1217. https://doi.org/10.1038/mt.2010.72

Preclinical PK and PD studies on 2′-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. / Heemskerk, Hans; De Winter, Christa; Van Kuik, Petra; Heuvelmans, Niki; Sabatelli, Patrizia; Rimessi, Paola; Braghetta, Paola; Van Ommen, Gert Jan B; De Kimpe, Sjef; Ferlini, Alessandra; Aartsma-Rus, Annemieke; Van Deutekom, Judith Ct.

In: Molecular Therapy, Vol. 18, No. 6, 06.2010, p. 1210-1217.

Research output: Contribution to journalArticle

Heemskerk, H, De Winter, C, Van Kuik, P, Heuvelmans, N, Sabatelli, P, Rimessi, P, Braghetta, P, Van Ommen, GJB, De Kimpe, S, Ferlini, A, Aartsma-Rus, A & Van Deutekom, JC 2010, 'Preclinical PK and PD studies on 2′-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model', Molecular Therapy, vol. 18, no. 6, pp. 1210-1217. https://doi.org/10.1038/mt.2010.72
Heemskerk, Hans ; De Winter, Christa ; Van Kuik, Petra ; Heuvelmans, Niki ; Sabatelli, Patrizia ; Rimessi, Paola ; Braghetta, Paola ; Van Ommen, Gert Jan B ; De Kimpe, Sjef ; Ferlini, Alessandra ; Aartsma-Rus, Annemieke ; Van Deutekom, Judith Ct. / Preclinical PK and PD studies on 2′-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. In: Molecular Therapy. 2010 ; Vol. 18, No. 6. pp. 1210-1217.
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