#apaperaday: Dystrophin Expressing Chimeric (DEC) Cell Therapy for Duchenne Muscular Dystrophy: A First-in-Human Study with Minimum 6 Months Follow-up

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: dystrophin Expressing Chimeric (DEC) Cell Therapy for Duchenne Muscular Dystrophy: A First-in-Human Study with Minimum 6 Months Follow-up

A paper from Heydemann et al on a clinical trial with dystrophin expressing chimeric stem cells in 3 duchenne patients from in stem cell reviews and reports. Doi 10.1007/s12015-023-10530-4.

Duchenne is caused by lack of dystrophin which leads to chronic loss of muscle tissue and function. Stem cell therapy would involve transplanting stem cells that repair muscle damage and express dystrophin.

Stem cells from donors can be used but that would require immunosuppression to prevent rejection. Stem cells from patients would not require this but these cells would have to be manipulated to allow dystrophin expression. The main challenge for stem cell therapy for muscle diseases is that stem cells do not go to muscle after systemic treatment in veins or arteries and do not move after local injections into muscle or heart.

Authors propose a solution for delivery and immunogenicity with chimeric stem cells that are injected into bones and then go to muscle from there. This involves isolating muscle stem cells from a muscle biopsy from the donor (father) and the patients and fusing them together.

Rather than injecting the cells into the blood, they are transplanted into the pelvic (iliac crest) bones. Authors claim that this worked in mdx mice —> see previous #apaperaday for my (not that positive) thoughts on that study.

Here 3 Duchenne patients were included so far: 2 ambulant 6 year olds and 1 non ambulant 15 year old. Primary goal of the study was to evaluate safety. No adverse events were reported in the 3 treated patients and no antibodies against the HLA proteins of the fathers were detected.

Authors then go in detail about the functional analyses of each patient. Both 6 year olds improve in the distance walked and strength – as would be expected from natural history (increases in function and strength until ~7 years) but authors claim this is a treatment effect.

Performance upper limb evaluation is meaningless in young patients as they are at the ceiling of the scale. Activity increases for patient 1 but I object to how authors present it: baseline is a few weeks after transplantation so perhaps there is a decreased activity due to this.

Then activity increases and then declines. Authors mention only maximum activity in the text and not the decline. Note that the baseline is not before treatment but several weeks after treatment. It is possible there is a seasonal effect involved.

Most children are more active in summer than winter. Authors do not discuss this at all. The nonambulant patient shows an increase in the PUL test and regained hand to mouth function. This is relevant BUT this is an open label study so a placebo effect is possible.

We should not overinterpret this one finding (like the authors do). Another consideration the authors do not mention is the fact that transplanted cells will produce growth factors that have a positive effect on muscle strength and PUL (as shown by capricorn in their trial).

It is possible effects seen are due to the growth factors rather than stem cells becoming muscle. This would fit with the initial increase and then decline when the transplanted cells die and stop producing growth factors (this is why Capricorn treats every 3 months).

On that topic: it is unknown whether the stemcells do go into muscle and restore dystrophin expression. Authors claim doing an open biopsy pre and post treatment was not done due to safety concerns as patients would have to be put under anesthesia for this procedure.

Note: for the treatment a biopsy is taken from the patient under anesthesia. So baseline biopsy can be obtained then. Also for the injection into bone patients are under anesthesia. For the treatment biopsy authors could consider a needle biopsy if they worry about anesthesia.

Authors discuss that their pilot data confirms safety and efficacy. I strongly object. It shows preliminary safety (only 3 patients so far) and nothing can be concluded about efficacy so far: Data are very preliminary, improvements in the ambulatory patients are expected without treatment, and no trajectories were measured before the treatment so one cannot make conclusions about trajectories changing. Finally, patients decline after initial increase

Authors claim their treatments stabilizes heart function: the 6 year olds probably have no pathology yet and for the 15 year old patient the timeline of 13 months is too short to conclude a stabilization.

Authors use motor unit potential with EMG as a biomarker for muscle function. I’m not an EMG specialist so I do not know how relevant this is – the fact that no one else is using this in Duchenne trials makes me wonder though.

I like that authors share preliminary data, but I do not like (understatement) they claim efficacy while nothing can be concluded so far, and authors do not provide required context (expect 6 year olds to improve anyway).

This type of communication leads to false hope with families and false expectations. This means it is difficult to make a proper risk assessment for patients for an extremely invasive and burdensome trial. An example of how NOT to publish about a clinical trial.