Functional muscle recovery following dystrophin and myostatin exon splice modulation in aged mdx mice

Duchenne muscular dystrophy (DMD) is a rare genetic disease affecting 1 in 3500-5000 newborn boys. It is due to mutations in the DMD gene with a consequent lack of dystrophin protein that leads to deterioration of myofibres and their replacement with fibro-adipogenic tissue. Out-of-frame mutations i...

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Bibliographic Details
Published in:Human molecular genetics 2019-09, Vol.28 (18), p.3091-3100
Main Authors: Lu-Nguyen, Ngoc, Ferry, Arnaud, Schnell, Frederick J, Hanson, Gunnar J, Popplewell, Linda, Dickson, George, Malerba, Alberto
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Dystrophin - genetics
Dystrophin - metabolism
Exons
Gene Expression Regulation
Immunohistochemistry
Life Sciences
Mice
Mice, Inbred mdx
Muscles - metabolism
Muscles - pathology
Muscles - physiopathology
Muscular Dystrophy, Duchenne - genetics
Muscular Dystrophy, Duchenne - metabolism
Muscular Dystrophy, Duchenne - pathology
Muscular Dystrophy, Duchenne - physiopathology
Myostatin - genetics
Myostatin - metabolism
RNA Splicing
RNA, Messenger - genetics
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Summary:Duchenne muscular dystrophy (DMD) is a rare genetic disease affecting 1 in 3500-5000 newborn boys. It is due to mutations in the DMD gene with a consequent lack of dystrophin protein that leads to deterioration of myofibres and their replacement with fibro-adipogenic tissue. Out-of-frame mutations in the DMD gene can be modified by using antisense oligonucleotides (AONs) to promote skipping of specific exons such that the reading frame is restored and the resulting protein produced, though truncated, is functional. We have shown that AONs can also be used to knock down myostatin, a negative regulator of muscle growth and differentiation, through disruption of the transcript reading frame, and thereby enhance muscle strength. In young mdx mice, combined dystrophin and myostatin exon skipping therapy greatly improved DMD pathology, compared to the single dystrophin skipping approach. Here we show that in aged (>15-month-old) mdx mice, when the pathology is significantly more severe and more similar to the one observed in DMD patients, the effect of the combined therapy is slightly attenuated but still beneficial in improving the disease phenotype. These results confirm the beneficial outcome of the combination approach and support its translation into DMD clinical trials.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddz125