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Intraperitoneal administration of phosphorothioate antisense oligodeoxynucleotide against splicing enhancer sequence induced exon skipping in dystrophin mRNA expressed in mdx skeletal muscle.
Brain Dev. 2005 Oct; 27(7):488-93.BD

Abstract

Antisense oligodeoxynucleotide against the splicing enhancer sequence (SES) in exon 19 of the dystrophin gene have been shown to induce exon 19 skipping and promote the expression of internally deleted dystrophin by correcting the translational reading frame in the cultured Duchenne muscular dystrophy (DMD) myocytes with the deletion of exon 20. Transfection of the antisense oligodeoxynucleotide, therefore, has been proposed as a promising means for therapeutic modification of dystrophin mRNA of DMD, a fatal disorder caused by defects in the dystrophin gene. A systemic delivery method targeting the large number of diseased muscles remains to be established for clinical application of antisense oligodeoxynucleotide. In this study, we investigated capability of oligodeoxynucleotide transfer into the skeletal muscles of mdx mouse, a mouse model of DMD. Thirty-one mer phosphorothioate oligodeoxynucleotide complementary to the SES of dystrophin exon 19 was intraperitoneally administered to mdx mice without any carrier. Histochemical study disclosed that fluorescence-labeled oligodeoxynucleotide appeared in the nuclei of femoral skeletal muscle cell at the second day after injection of 20 mg/kg BW oligodeoxynucleotide, and still visible at 14th day. Reverse transcription (RT)-PCR analysis of dystrophin transcript in these cells disclosed that a proportion of it showed skipping of exon 19 from second to seventh day after injection. These results showed that the intraperitoneally administered oligodeoxynucleotide could be transfected to nucleus of mdx skeletal muscle without any carrier and was able to induce exon skipping in vivo.

Authors+Show Affiliations

Department of Pediatrics, Graduate School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. takesima@med.kobe-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16198206

Citation

Takeshima, Yasuhiro, et al. "Intraperitoneal Administration of Phosphorothioate Antisense Oligodeoxynucleotide Against Splicing Enhancer Sequence Induced Exon Skipping in Dystrophin mRNA Expressed in Mdx Skeletal Muscle." Brain & Development, vol. 27, no. 7, 2005, pp. 488-93.
Takeshima Y, Yagi M, Wada H, et al. Intraperitoneal administration of phosphorothioate antisense oligodeoxynucleotide against splicing enhancer sequence induced exon skipping in dystrophin mRNA expressed in mdx skeletal muscle. Brain Dev. 2005;27(7):488-93.
Takeshima, Y., Yagi, M., Wada, H., & Matsuo, M. (2005). Intraperitoneal administration of phosphorothioate antisense oligodeoxynucleotide against splicing enhancer sequence induced exon skipping in dystrophin mRNA expressed in mdx skeletal muscle. Brain & Development, 27(7), 488-93.
Takeshima Y, et al. Intraperitoneal Administration of Phosphorothioate Antisense Oligodeoxynucleotide Against Splicing Enhancer Sequence Induced Exon Skipping in Dystrophin mRNA Expressed in Mdx Skeletal Muscle. Brain Dev. 2005;27(7):488-93. PubMed PMID: 16198206.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intraperitoneal administration of phosphorothioate antisense oligodeoxynucleotide against splicing enhancer sequence induced exon skipping in dystrophin mRNA expressed in mdx skeletal muscle. AU - Takeshima,Yasuhiro, AU - Yagi,Mariko, AU - Wada,Hiroko, AU - Matsuo,Masafumi, PY - 2004/05/18/received PY - 2004/12/27/revised PY - 2004/12/27/accepted PY - 2005/10/4/pubmed PY - 2005/12/16/medline PY - 2005/10/4/entrez SP - 488 EP - 93 JF - Brain & development JO - Brain Dev VL - 27 IS - 7 N2 - Antisense oligodeoxynucleotide against the splicing enhancer sequence (SES) in exon 19 of the dystrophin gene have been shown to induce exon 19 skipping and promote the expression of internally deleted dystrophin by correcting the translational reading frame in the cultured Duchenne muscular dystrophy (DMD) myocytes with the deletion of exon 20. Transfection of the antisense oligodeoxynucleotide, therefore, has been proposed as a promising means for therapeutic modification of dystrophin mRNA of DMD, a fatal disorder caused by defects in the dystrophin gene. A systemic delivery method targeting the large number of diseased muscles remains to be established for clinical application of antisense oligodeoxynucleotide. In this study, we investigated capability of oligodeoxynucleotide transfer into the skeletal muscles of mdx mouse, a mouse model of DMD. Thirty-one mer phosphorothioate oligodeoxynucleotide complementary to the SES of dystrophin exon 19 was intraperitoneally administered to mdx mice without any carrier. Histochemical study disclosed that fluorescence-labeled oligodeoxynucleotide appeared in the nuclei of femoral skeletal muscle cell at the second day after injection of 20 mg/kg BW oligodeoxynucleotide, and still visible at 14th day. Reverse transcription (RT)-PCR analysis of dystrophin transcript in these cells disclosed that a proportion of it showed skipping of exon 19 from second to seventh day after injection. These results showed that the intraperitoneally administered oligodeoxynucleotide could be transfected to nucleus of mdx skeletal muscle without any carrier and was able to induce exon skipping in vivo. SN - 0387-7604 UR - https://www.unboundmedicine.com/medline/citation/16198206/Intraperitoneal_administration_of_phosphorothioate_antisense_oligodeoxynucleotide_against_splicing_enhancer_sequence_induced_exon_skipping_in_dystrophin_mRNA_expressed_in_mdx_skeletal_muscle_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0387-7604(05)00009-4 DB - PRIME DP - Unbound Medicine ER -