Preclinical PK and PD studies on 2'-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. 2010

Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

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.

UI MeSH Term Description Entries
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005455 Fluorescent Antibody Technique Test for tissue antigen using either a direct method, by conjugation of antibody with fluorescent dye (FLUORESCENT ANTIBODY TECHNIQUE, DIRECT) or an indirect method, by formation of antigen-antibody complex which is then labeled with fluorescein-conjugated anti-immunoglobulin antibody (FLUORESCENT ANTIBODY TECHNIQUE, INDIRECT). The tissue is then examined by fluorescence microscopy. Antinuclear Antibody Test, Fluorescent,Coon's Technique,Fluorescent Antinuclear Antibody Test,Fluorescent Protein Tracing,Immunofluorescence Technique,Coon's Technic,Fluorescent Antibody Technic,Immunofluorescence,Immunofluorescence Technic,Antibody Technic, Fluorescent,Antibody Technics, Fluorescent,Antibody Technique, Fluorescent,Antibody Techniques, Fluorescent,Coon Technic,Coon Technique,Coons Technic,Coons Technique,Fluorescent Antibody Technics,Fluorescent Antibody Techniques,Fluorescent Protein Tracings,Immunofluorescence Technics,Immunofluorescence Techniques,Protein Tracing, Fluorescent,Protein Tracings, Fluorescent,Technic, Coon's,Technic, Fluorescent Antibody,Technic, Immunofluorescence,Technics, Fluorescent Antibody,Technics, Immunofluorescence,Technique, Coon's,Technique, Fluorescent Antibody,Technique, Immunofluorescence,Techniques, Fluorescent Antibody,Techniques, Immunofluorescence,Tracing, Fluorescent Protein,Tracings, Fluorescent Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings
D016189 Dystrophin A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as SPECTRIN and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa.
D016372 RNA, Antisense RNA molecules which hybridize to complementary sequences in either RNA or DNA altering the function of the latter. Endogenous antisense RNAs function as regulators of gene expression by a variety of mechanisms. Synthetic antisense RNAs are used to effect the functioning of specific genes for investigative or therapeutic purposes. Antisense RNA,Anti-Sense RNA,Anti Sense RNA,RNA, Anti-Sense
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D054735 Phosphorothioate Oligonucleotides Modified oligonucleotides in which one of the oxygens of the phosphate group is replaced with a sulfur atom. Oligonucleotides, Phosphorothioate
D018101 Mice, Inbred mdx A strain of mice arising from a spontaneous MUTATION (mdx) in inbred C57BL mice. This mutation is X chromosome-linked and produces viable homozygous animals that lack the muscle protein DYSTROPHIN, have high serum levels of muscle ENZYMES, and possess histological lesions similar to human MUSCULAR DYSTROPHY. The histological features, linkage, and map position of mdx make these mice a worthy animal model of DUCHENNE MUSCULAR DYSTROPHY. Mice, mdx,Mouse, Inbred mdx,Mouse, mdx,Inbred mdx Mice,Inbred mdx Mouse,mdx Mice,mdx Mouse
D020133 Reverse Transcriptase Polymerase Chain Reaction A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols. Polymerase Chain Reaction, Reverse Transcriptase,Reverse Transcriptase PCR,PCR, Reverse Transcriptase,Transcriptase PCR, Reverse

Related Publications

Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
April 2019, Nucleic acid therapeutics,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
July 2015, Journal of materials chemistry. B,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
June 2013, Nucleic acid therapeutics,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
April 2024, RSC advances,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
January 2004, Nucleic acids research,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
May 2022, Organic & biomolecular chemistry,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
June 1997, Antisense & nucleic acid drug development,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
December 2019, Nucleic acid therapeutics,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
May 2006, Genetic vaccines and therapy,
Hans Heemskerk, and Christa de Winter, and Petra van Kuik, and Niki Heuvelmans, and Patrizia Sabatelli, and Paola Rimessi, and Paola Braghetta, and Gert-Jan B van Ommen, and Sjef de Kimpe, and Alessandra Ferlini, and Annemieke Aartsma-Rus, and Judith C T van Deutekom
September 2014, ChemMedChem,
Copied contents to your clipboard!