1 2 aim

#apaperaday: Immune-mediated myositis following gene therapy for Duchenne muscular dystrophy: a case report

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Immune-mediated myositis following gene therapy for Duchenne muscular dystrophy: a case report

Today’s pick from journal of neurology by Iannaccone et al: a case report of a Duchenne patient who had an auto-immune response to micro-dystrophin after elevidys treatment. DOI: 10.1007/s00415-024-12431-z

AAV gene therapy is in clinical development by several companies for slightly different micro-dystrophins (4) & different AAV serotypes (3, AAV74, AAV8 and AAV9). 1 gene therapy (Elevidys) is approved in the USA – since last week full approval for ambulatory patients age 4 and up.

For non ambulatory patients there is accelerated approval. However, patients with a deletion of exon 8 and 9 are excluded from the label as there is a risk of an auto-immune response to the micro-dystrophin. So far 6 such cases have been reported (for various micro-dystrophins).

These cases had long deletions at the beginning of the dystrophin protein, except 1 who had a deletion of exon 8-9. The overlapping region of the deletions was the hinge 1 domain, while likely is immunogenic. Why does this not cause an immune response in all Duchenne patients?

This is because patients with the more common deletions (in the central rod domain, between exon 40 and 55) can make the first part of dystrophin. This is not functional and not stable, but the immune system will have been exposed to this and thus recognizes hinge 1 as ‘self’.

Patients with a deletion at the beginning of the dystrophin gene however, will not make these unstable proteins with hinge 1 as the code for this is deleted. THUS, when a micro-dystrophin protein is suddenly expressed in muscle, the immune system sees something new and attacks.

The case report describes the consequences of this event in one case treated with elevidys (but note that it also happened for other micro-dystrophins developed by others in other cases). The patient was 9 year old & ambulant at the time of gene therapy treatment in a trial.

He had a deletion of exon 3-43 (so could not produce hinge 1). 1 month post gene therapy he had an acute onset of muscle weakness, while he was still on a high steroid dose as part of the gene therapy trial. He had a changed voice, swallowing problems & breathing difficulties.

Furthermore, he could not walk independently and could not sit without assistance. Blood levels were normal, except his CK was elevated (28 kU/l). He was admitted to ICU and given ventilatory support and tube feeding and 6 rounds of plasma exchange (to remove antibodies).

Fortunately, this resulted in him recovering a normal voice. He was given more immune suppression and regained the ability to walk with slight assistance. 22 months after the event, he shows frequent falls and needs a wheelchair for long distances. Respiratory function is OK.

A biopsy was done which showed very low levels of micro-dystrophin – which makes sense as likely all the fibers expressing micro-dystrophin were destroyed by the immune system. Authors discuss that they could see T-cells targeting micro-dystrophin but not antibodies.

However, the plasma exchange was done, so this may have removed antibodies. They also argue that by the time the biopsy was done, the boy had received severe immune suppression, which may also have altered the immune response (from the original acute attack).

I appreciate authors reporting this case as it outlines why it is important not to treat patients with specific deletions with micro-dystrophins. For these patients the treatment will make things worse, as micro-dystrophin expressing fibers are removed.

So there is no benefit (micro-dystrophin) but there is a loss of muscle mass and an acute situation that could potentially be lethal. Fortunately this patient survived and fortunately we now are aware of this risk also because companies involved shared data and reported.