DOI: 10.1073/pnas.0406700102. Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles

Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles

10.1073/pnas.0406700102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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.

Bibliography

Lu, Q. L., Rabinowitz, A., Chen, Y. C., Yokota, T., Yin, H., Alter, J., Jadoon, A., Bou-Gharios, G., & Partridge, T. (2004). Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proceedings of the National Academy of Sciences, 102(1), 198â203.

Authors 9

Qi Long Lu (first)
Adam Rabinowitz (additional)
Yun Chao Chen (additional)
Toshifumi Yokota (additional)
HaiFang Yin (additional)
Julia Alter (additional)
Atif Jadoon (additional)
George Bou-Gharios (additional)
Terence Partridge (additional)

References 22 Referenced 341

10.1016/0092-8674(87)90579-4
Laing N. G. (1993) in Molecular and Cell Biology of Muscular Dystrophy ed. Partridge T. (Chapman & Hall London).
10.2174/1568009013334124
10.1073/pnas.85.15.5507
10.1073/pnas.90.18.8673
10.1002/jgm.295
10.1016/S0960-8966(02)00086-X
10.1038/343180a0
10.1016/S0006-291X(02)00362-5
10.1083/jcb.148.5.985
10.1038/nm897
10.1073/pnas.98.1.42
10.1177/002215549804600813
10.1002/mus.10243
10.1038/sj.gt.3301874
10.1038/sj.gt.3301829
10.1038/nm1085
10.1038/4033
10.1016/j.nmd.2003.09.004
10.1016/S0960-8966(02)00085-8
10.1016/j.ymthe.2004.05.031
10.1038/sj.gt.3302313

Dates

Type	When
Created	20 years, 8 months ago (Dec. 17, 2004, 8:17 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 8:31 a.m.)
Indexed	4 days, 4 hours ago (Aug. 28, 2025, 8:23 a.m.)
Issued	20 years, 8 months ago (Dec. 17, 2004)
Published	20 years, 8 months ago (Dec. 17, 2004)
Published Online	20 years, 8 months ago (Dec. 17, 2004)
Published Print	20 years, 7 months ago (Jan. 4, 2005)

Funders 0

None

BibTeX

@article{Lu_2004, title={Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0406700102}, DOI={10.1073/pnas.0406700102}, number={1}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Lu, Qi Long and Rabinowitz, Adam and Chen, Yun Chao and Yokota, Toshifumi and Yin, HaiFang and Alter, Julia and Jadoon, Atif and Bou-Gharios, George and Partridge, Terence}, year={2004}, month=dec, pages={198–203} }

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