Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles.
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| Title: | Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. |
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| Authors: | Qi Long Lu1 qi.Iu@carolinashealthcare.org, Rabinowitz, Adam2, Yun Chao Chen3, Yokota, Toshifumi2, HaiFang Yin2, Alter, Julia2, Jadoon, Atif2, Bou-Gharios, George4, Partridge, Terence2 |
| Source: | Proceedings of the National Academy of Sciences of the United States of America. 1/4/2005, Vol. 102 Issue 1, p198-203. 6p. |
| Subjects: | Oligonucleotides, Gene expression, Duchenne muscular dystrophy, Dystrophin, Genetic transcription, Serum |
| Abstract: | Antisense oligonucleotide-mediated alternative splicing has great potential for treatment of Duchenne muscular dystrophy (DMD) caused by mutations within nonessential regions of the dystrophin gene. We have recently shown in the dystrophic mdx mouse that exon 23, bearing a nonsense mutation, can be skipped after intramuscular injection of a specific 2'-O-methyl phosphorothioate antisense oligoribonucleotide (2OMeAO). This skipping created a shortened, but in-frame, transcript that is translated to produce near-normal levels of dystrophin expression. This expression, in turn, led to improved muscle function. However, because DMD affects muscles body-wide, effective treatment requires dystrophin induction ideally in all muscles. Here, we show that systemic delivery of specific 2OMeAOs, together with the triblock copolymer F127, induced dystrophin expression in all skeletal muscles but not in cardiac muscle of the mdx dystrophic mice. The highest dystrophin expression was detected in diaphragm, gastrocnemius, and intercostal muscles. Large numbers of fibers with near-normal level of dystrophin were observed in focal areas, Three injections of 2OMeAOs at weekly intervals enhanced the levels of dystrophin. Dystrophin mRNA lacking the targeted exon 23 remained detectable 2 weeks after injection. No evidence of tissue damage was detected after 2OMeAO and F127 treatment either by serum analysis or histological examination of liver, kidney, lung, and muscles. The simplicity and safety of the antisense protocol provide a realistic prospect for treatment of the majority of DMD mutations. We conclude that a significant therapeutic effect may be achieved by further optimization in dose and regime of administration of antisense oligonucleotide. [ABSTRACT FROM AUTHOR] |
| Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 15912892 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Qi+Long+Lu%22">Qi Long Lu</searchLink><relatesTo>1</relatesTo><i> qi.Iu@carolinashealthcare.org</i><br /><searchLink fieldCode="AR" term="%22Rabinowitz%2C+Adam%22">Rabinowitz, Adam</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Yun+Chao+Chen%22">Yun Chao Chen</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Yokota%2C+Toshifumi%22">Yokota, Toshifumi</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22HaiFang+Yin%22">HaiFang Yin</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Alter%2C+Julia%22">Alter, Julia</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Jadoon%2C+Atif%22">Jadoon, Atif</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Bou-Gharios%2C+George%22">Bou-Gharios, George</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Partridge%2C+Terence%22">Partridge, Terence</searchLink><relatesTo>2</relatesTo> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 1/4/2005, Vol. 102 Issue 1, p198-203. 6p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Oligonucleotides%22">Oligonucleotides</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression%22">Gene expression</searchLink><br /><searchLink fieldCode="DE" term="%22Duchenne+muscular+dystrophy%22">Duchenne muscular dystrophy</searchLink><br /><searchLink fieldCode="DE" term="%22Dystrophin%22">Dystrophin</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+transcription%22">Genetic transcription</searchLink><br /><searchLink fieldCode="DE" term="%22Serum%22">Serum</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Antisense oligonucleotide-mediated alternative splicing has great potential for treatment of Duchenne muscular dystrophy (DMD) caused by mutations within nonessential regions of the dystrophin gene. We have recently shown in the dystrophic mdx mouse that exon 23, bearing a nonsense mutation, can be skipped after intramuscular injection of a specific 2'-O-methyl phosphorothioate antisense oligoribonucleotide (2OMeAO). This skipping created a shortened, but in-frame, transcript that is translated to produce near-normal levels of dystrophin expression. This expression, in turn, led to improved muscle function. However, because DMD affects muscles body-wide, effective treatment requires dystrophin induction ideally in all muscles. Here, we show that systemic delivery of specific 2OMeAOs, together with the triblock copolymer F127, induced dystrophin expression in all skeletal muscles but not in cardiac muscle of the mdx dystrophic mice. The highest dystrophin expression was detected in diaphragm, gastrocnemius, and intercostal muscles. Large numbers of fibers with near-normal level of dystrophin were observed in focal areas, Three injections of 2OMeAOs at weekly intervals enhanced the levels of dystrophin. Dystrophin mRNA lacking the targeted exon 23 remained detectable 2 weeks after injection. No evidence of tissue damage was detected after 2OMeAO and F127 treatment either by serum analysis or histological examination of liver, kidney, lung, and muscles. The simplicity and safety of the antisense protocol provide a realistic prospect for treatment of the majority of DMD mutations. We conclude that a significant therapeutic effect may be achieved by further optimization in dose and regime of administration of antisense oligonucleotide. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1073/pnas.0406700102 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 6 StartPage: 198 Subjects: – SubjectFull: Oligonucleotides Type: general – SubjectFull: Gene expression Type: general – SubjectFull: Duchenne muscular dystrophy Type: general – SubjectFull: Dystrophin Type: general – SubjectFull: Genetic transcription Type: general – SubjectFull: Serum Type: general Titles: – TitleFull: Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Qi Long Lu – PersonEntity: Name: NameFull: Rabinowitz, Adam – PersonEntity: Name: NameFull: Yun Chao Chen – PersonEntity: Name: NameFull: Yokota, Toshifumi – PersonEntity: Name: NameFull: HaiFang Yin – PersonEntity: Name: NameFull: Alter, Julia – PersonEntity: Name: NameFull: Jadoon, Atif – PersonEntity: Name: NameFull: Bou-Gharios, George – PersonEntity: Name: NameFull: Partridge, Terence IsPartOfRelationships: – BibEntity: Dates: – D: 04 M: 01 Text: 1/4/2005 Type: published Y: 2005 Identifiers: – Type: issn-print Value: 00278424 Numbering: – Type: volume Value: 102 – Type: issue Value: 1 Titles: – TitleFull: Proceedings of the National Academy of Sciences of the United States of America Type: main |
| ResultId | 1 |
