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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

From @worldmusclesociety.org #WMS2025 meeting where Lilly Winter presented on plectin Wednesday: i think it is more likely that this #apaperaday case has a pathogenic variant in plectin because that leads to muscle weakness and skin disease. See also e.g. pubmed.ncbi.nlm.nih.gov/15810881/

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Next week #apaperaday will feature a bit of everything, until we move to an N=1 collaborative and Oligonucleotide Therapeutics Society themed series starting next Saturday (N1C meeting, followed by #OTS2025 meeting), which will of course feature oligonucleotide research.

Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Finally, authors end by saying with something I wholeheartedly agree with: the rat model is not there to replace other model, it is in complement to other models. Each model has its opportunities and limitations. So one should ask the right question to the right model.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

They also reflect that more study is needed to further elucidate the brain comorbidity in different DMD rats (due to the presence or absence of one or more brain dystrophin isoforms).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

The rats have been used to test therapeutic compounds, either aiming to restore dystrophin, or address pathology. Authors discuss that a challenge is that it is currently difficult to compare the different rat models to eachother as no standardized procedures were used.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

The DMD rat models show cardiac inflammation and fibrosis already at 3 months, while the Becker rats develop this later (6-12 months). The DMD rats also have reduced brain volumes, increased GABA in the hippocampus and behavioral issues (similar to some DMD patients).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

The DMD rats show muscle damage and necrosis and fibrosis and fat infiltration and inflammation. The Becker rat models show this as well but at a lesser extent. The exon 45 deletion rats fall in between Becker and DMD (those with no or very little dystrophin).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Becker rat models also exist: a deletion of exon 3-16 and a deletion of exon 45-47 (most common deletion in Becker patients). Finally a rat model with a deletion of rat exon 45 exists, which skips exon 44 at low level and thus produces some dystrophin (just like in patients with this mutation).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

A huge table containing specifics of each line is enclosed in the paper. Rat models for DMD: point mutation in exon 23 (similar to mdx mouse), deletion exon 3, deletion exon 16, deletion exon 22-26, deletion exon 52, duplication exon 10-17 & small deletion within exon 13 of the rat dystrophin gene.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Mice are used most often in preclinical development, but have a milder disease. Larger animal models exists as well including dogs, pigs, rabbits and non human primates and the focus of this review: rats. Authors outline the different rats that have been generated.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

When a partially functional dystrophin can be produced, people develop Becker muscular dystrophy – which has a later onset of symptoms and slower progression compared to DMD. Authors introduce that there are many animal models for DMD, including mdx mice.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Duchenne muscular dystrophy (DMD) is caused by lack of dystrophin. This leads to chronic muscle damage, inflammation, and replacement of muscle by fat and adipose tissues. Later patients also develop cardiomyopathy and a subset of patients also has cognitive and/or behavior comorbidities.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

#apaperaday the last #WMS2025 @worldmusclesociety.org themed paper, a review by Relaix et al on rat models for Duchenne muscular dystrophy, published in Skeletal Muscle and specifically flagged by the journal for #WDAD2025 @worldduchenne.bsky.social. DOI: 10.1186/s13395-025-00395-1

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

I hope it is possible to find a way to treat these patients as the therapy is clearly effective, however, it is currently also clearly not safe.
Tomorrow the last #WMS2025 themed paper, which will be preclinical, featuring a review paper on a new Duchenne animal model. Stay tuned

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Currently 1/3 patients who were treated does not need a ventilator anymore and they developed milestones. Studies are ongoing to study the liver complications and see if it can be predicted who will and who will not develop them and how to properly monitor.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

During the trial 3 patients in the control group passed away due to MTM; as mentioned 4 patients in the treated group died from liver disease. Other side effects were seen for the treated patients as well, including myocarditis (inflammation of the heart) and thrombocytopenia (too little platelets).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

The patients who were treated required less hours of ventilation, had improved respiratory muscle strength and improved motor function. Also some developed motor skills such as sitting and standing and walking (not commonly seen in MTM patients).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

After the first 3 patients were treated with the low dose, 17 patients were treated with the high dose. Sadly 3 died from liver failure. Then the trial continued with the lower dose and 4 patients were treated. After one patient died here from liver failure, the trial was put on hold by the FDA.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Note that 2 of the 14 untreated patients were supposed to get the treatment but did not. Before the treatment the baselines of the patients in the groups on average were similar, with if anything the treated groups having longer ventilation duration and lower respiratory strength.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

In animal models this showed promise and therefore it was tested in a clinical trial. 26 patients were included in the clinical trial: 7 received a low dose and 17 a high dose, while 14 patients were not treated.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Half of the affected patients die within the first 18 months of life, and those who survive usually do not develop and do not learn to sit, stand or walk.
Resamirigene bilparvovec is a gene therapy that contains the gene code for the myotubulin protein.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

X-linked myotubular myopathy is a severe muscle disease, that primarily occurs in boys as the gene that is affected is located on the X-chromosome. This gene, the MTM1 gene, codes for a protein called myotubulin. Lacking this protein patients develop severe muscle weakness.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

The original publication in @thelancet.com Neurology also featured when #apaperaday was still on Twitter: x.com/oligogirl/st... (The X search function is horrific as a side note). I really appreciate the authors took the effort to draft a plain language paper about the clinical trial.

x.com

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

#apaperaday Today the @worldmusclesociety.org #WMS2025 themed series continues with a pick from Shieh et al in Therapeutic Advances in Rare Diseases. It is a plain language summary of a previous publication on the gene therapy trial in myotubular myopathy patients. DOI 10.1177/26330040251362885

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 4d

I appreciate authors sharing this case and while it is sad the treatment had to be stopped and the patient now cannot be retreated/given the rest of the dose, I am glad the patient is otherwise fine.

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