Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. In DMD patients and in a corresponding pig model with a deletion of DMD exon 52 (DMDΔ52), expression of an internally shortened dystrophin can be achieved by skipping of DMD exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated DMDΔ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD). DMDΔ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in DMDΔ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of DMDΔ51-52 pigs and its absence in DMDΔ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in DMDΔ52 vs. wild-type (WT) samples, was normalized in DMDΔ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in DMDΔ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in DMDΔ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of DMD exon 51 in DMDΔ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of DMDΔ51-52 pigs will show if they develop symptoms of the milder BMD.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 120(2023), 29 vom: 18. Juli, Seite e2301250120 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Stirm, Michael [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Becker muscular dystrophy |
|---|
| Anmerkungen: |
Date Completed 12.07.2023 Date Revised 09.11.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1073/pnas.2301250120 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359299113 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359299113 | ||
| 003 | DE-627 | ||
| 005 | 20231226080557.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.2301250120 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1197.xml |
| 035 | |a (DE-627)NLM359299113 | ||
| 035 | |a (NLM)37428903 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Stirm, Michael |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Systemic deletion of DMD exon 51 rescues clinically severe Duchenne muscular dystrophy in a pig model lacking DMD exon 52 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.07.2023 | ||
| 500 | |a Date Revised 09.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. In DMD patients and in a corresponding pig model with a deletion of DMD exon 52 (DMDΔ52), expression of an internally shortened dystrophin can be achieved by skipping of DMD exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated DMDΔ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD). DMDΔ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in DMDΔ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of DMDΔ51-52 pigs and its absence in DMDΔ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in DMDΔ52 vs. wild-type (WT) samples, was normalized in DMDΔ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in DMDΔ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in DMDΔ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of DMD exon 51 in DMDΔ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of DMDΔ51-52 pigs will show if they develop symptoms of the milder BMD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Becker muscular dystrophy | |
| 650 | 4 | |a Duchenne muscular dystrophy | |
| 650 | 4 | |a exon skipping | |
| 650 | 4 | |a pathology | |
| 650 | 4 | |a pig model | |
| 650 | 7 | |a Dystrophin |2 NLM | |
| 650 | 7 | |a Proteome |2 NLM | |
| 700 | 1 | |a Shashikadze, Bachuki |e verfasserin |4 aut | |
| 700 | 1 | |a Blutke, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Kemter, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Lange, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Stöckl, Jan B |e verfasserin |4 aut | |
| 700 | 1 | |a Jaudas, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Laane, Laeticia |e verfasserin |4 aut | |
| 700 | 1 | |a Kurome, Mayuko |e verfasserin |4 aut | |
| 700 | 1 | |a Keßler, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Zakhartchenko, Valeri |e verfasserin |4 aut | |
| 700 | 1 | |a Bähr, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Klymiuk, Nikolai |e verfasserin |4 aut | |
| 700 | 1 | |a Nagashima, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Walter, Maggie C |e verfasserin |4 aut | |
| 700 | 1 | |a Wurst, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Kupatt, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Fröhlich, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Eckhard |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 120(2023), 29 vom: 18. Juli, Seite e2301250120 |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
| 773 | 1 | 8 | |g volume:120 |g year:2023 |g number:29 |g day:18 |g month:07 |g pages:e2301250120 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.2301250120 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 120 |j 2023 |e 29 |b 18 |c 07 |h e2301250120 | ||