Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy

#apaperaday 

Prof. Annemieke Aartsma-Rus is taking on a challenge by reading and commenting on a paper a day. She shares her insights, findings and thoughts via her @oligogirl Twitter account. See below the overview of January 2023.

***

Prof. Aartsma-Rus reads and comments on the paper titled: Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy.

Bonus paper from New York on studying disease progression in Duchenne patients with no or very low dystrophin levels by De Feraudy et al in Annals Neurology doi 10.1002/ana.25951. This paper was mentioned at the PPMD USA summit by Craig MacDonald.

Duchenne patients make no or very low levels of dystrophin while Becker patients make low or normal levels of dystrophin that is internally deleted. It is now clear that most Duchenne patients make some dystrophin and that even levels of ~15% can be enough to result in Becker.

Also while Duchenne and Becker are still distinct diagnoses it is more and more clear that there is a spectrum of dystrophinopathy severity (severe Duchenne mild Duchenne severe Becker mild Becker carriers with symptoms).

While over a certain threshold more dystrophin does not lead to better function or slower progression the dystrophin levels restored in exon skipping trials are definitely in the linear range where more is better, authors here studied the disease progression of French patients with dystrophinopathy with no or very low dystrophin levels based on western blot analysis.

Out of 3880 patients in the database, 90 were selected: 42 expressing no dystrophin (<0.5%) on Western blot, 34 expressing less than 5% and 14 expressing more than 5%. I will focus on no dystrophin and 0.5-5% for the comparison (no vs low).

Patients with no dystrophin had earlier loss of ambulation, first symptoms, heart problems and earlier need for ventilatory support than patients with low dystrophin levels. Steroids delayed loss of ambulation and ataluren treatment did as well.

This fits with studies in mice and exon 44 skippable patients (expressing also low dystrophin levels). Authors discuss that these patients express dystrophin from birth so it is not the same as restoring it later in life (agreed!)

They also discuss the limitations:

1. Dystrophin levels were based on a single biopsy. If the biopsy was taken from fibrotic or fat tissue then the levels may not have been reflective of the muscle tissue. Also dystrophin levels in the heart may have been different.
2. This was a long term retrospective study and some patients were born in 1940. With time care improved (ventilatory support and steroids), which also will have had an impact on progression.
3. The western blot did not use a serial dilution as therefore is less sensitive than e.g. what is used in Sarepta trials. I appreciate the work and open discussion of limitations. The amount of patients in the database is impressive and it is good to see authors put it to good use.

#apaperaday

About Professor Annemieke Aartsma-Rus

Prof. Dr. Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. Since 2013 she has a visiting professorship at the Institute of Genetic Medicine of Newcastle University (UK).

Her work currently focuses on developing antisense-mediated exon skipping as a therapy for Duchenne muscular dystrophy. In addition, in collaborative efforts she aims to bridge the gap between different stakeholders (patients, academics, regulators and industry) involved in drug development for rare diseases.

In 2013 she was elected a member of the junior section of the Dutch Royal Academy of Sciences (KNAW), which consists of what are considered the top 50 scientists in the Netherlands under 45. From 2015 to 2022, she was selected as the most influential scientist in Duchenne muscular dystrophy by Expertscape.