#apaperaday: Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration

Today’s #openacademy2024 @eurordis themed pick is an example of authors believing so much in their approach they stop being critical. I have featured work from Budzynska et al before, now a review by them on their work in biomolecules DOI: 10.3390/biom14050575

The topic is chimeric cell therapy for Duchenne. Authors introduce the concept of chimerism: one being that has genetic information from multiple beings. In mythology the chimera (lion goat snake) is a fictional example, but this can happen in humans too: e.g. after a bone marrow transplantation, the recipient will have his own cells but bone marrow cells from the donor. In mothers sometimes a few cells from children can be found within tissues. However, these are all cases where each cell still has their own DNA.

Authors introduce the concept of fusing cells in the lab, so the resulting cell has DNA from 2 different origins. In theory, when you do this for Duchenne and a healthy individual the hope is you would get a chimeric cell able to make dystrophin and seen by a patient as ‘self’.

Thus there would not be an immune response, which would happen if you transplant donor cells from someone else. So far so good. However, the caveat is that stem cell treatment of muscle stem cells (myoblasts) or earlier stem cells (mesenchymal stem cells) is very inefficient: after injection into the blood, only very few cells will migrate into the muscle. Even after local injection in muscle, cells will stay put and not migrate. This means that there is no expected therapeutic effect: the muscle has pathology, a single cell is unable to counteract.

As a solution to this, authors propose injecting the chimeric cells in the pelvic bone, from where they should migrate to the skeletal muscle (not clear how or why this would work). Authors claim to have shown this in mdx mice, with dystrophin restoration (no reference provided)

So I dived into the literature & found a paper where they tested this in mdx mice. They claim 37% dystrophin, but what they mean in 37% of the cells started to make some dystrophin (see image below). I am not convinced by this image – there is no laminin counterstaining and wild type looks bad.

Authors also provide a table with all the preclinical and clinical work published on this topic. Note that ALL these paper are from the authors and that the 3 publications on the clinical trial are from the same trial with different times of follow up: https://www.mdpi.com/2218-273X/14/5/575

Authors also claim the treatment improves heart function. I explained this in an earlier #apaperaday: look at graph H: authors claim there is a cardiac effect as there is no deterioration for the high dose group (most right 3 bars), however.

If you look at the baseline you will see that the baseline is lower than that of the vehicle and the low dose group. So the mice receiving the high dose had a poor heart function at baseline and then did not get worse. They are as bad at day 90 as the vehicle and low dose.

Back to the review, written in the third person even though all the work reviewed is by the same authors as the publications they review. Authors mention the approach is tested in a clinical trial designed to treat 10 patients age 6-15, so far only 3 were treated (not mentioned).

There are now 3 papers on this trial published and 2 were featured in #apaperaday https://x.com/oligogirl/status/1649720014411276288 and https://x.com/oligogirl/status/1706219563602309466. Authors claim in the review paper the trial shows safety and efficacy (stable after a brief improvement and decline). However,

They treated 2 six year old patients, where the natural history will show improvement and then stability for most patients. So it is wishful thinking to conclude this was due to the treatment. Note that dystrophin analysis was not done in any of the patients in the trial.

Nevertheless, authors imply the treatment effects are due to dystrophin restoration. In their future perspective they now propose this same approach for patients with other muscle diseases (genetic and acquired and metabolic) and even motor neuron diseases like ALS.

They claim the long term engraftment is an asset. Note that all this speculation is based on a trial involving 3 patients and no control group and very poorly conducted preclinical studies with no analysis to confirm any engraftment.

At first I thought to ignore this group and their plethora of papers about the same topics/experiments/trial. However, patients and clinicians ask me about this approach because based on exposure (the many publications about the same things) they feel this may be something.

I guess from my rant it is clear this approach is not at all promising. I believe authors believe so much in their approach they only have to show that it works and forget the important aspect of academic research where you also do tests to show your hypothesis is wrong.