In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report
Today’s pick is from a journal of medical case reports by Nair et al: a Duchenne patient who also had Diamond-Blackfan anemia, for which he required a hematopoietic stem cell transplantation. Published in 2011. Doi 10.1186/1752-1947-5-216
I assume my followers know about Duchenne muscular dystrophy, but Diamond-Blackfan anemia may need an introduction: it is a rare congenital disease that occurs in ~5-10 per million births. Patients have a defect in early steps of erythropoiesis (production of red blood cells)
This leads to anemia. Treatment with steroids helps initially but most patients need regular transfusions by the age of 18 months. A transplantation of hematopoietic stem cells from healthy donors (that produce red blood cells) can cure this anemia & is successful in 85% of cases.
The authors introduce a 9 year old boy from North-Indian descent who was diagnosed at 8 months with Diamond-Blackfan anemia. By the age of 4 muscle weakness was noticed and he was also diagnosed with Duchenne muscular dystrophy. The patient needed regular transfusions from age 6.
Since one of his brothers was an HLA match, a stem cell transplantation was an option. The patient was pretreated (i.e. removing the original stem cells to make room for the donor stem cells). Engraftment was successful and blood levels are now normal! Hooray.
Authors mention that since the stem cell transplantation the patient appear to be stable. He was wheelchair dependent at the time of the transplant and still is in a wheelchair. However, he can sit 3 hours independently now for 45 months and CK levels have dropped.
Authors looked at chimerism in muscle biopsies (i.e. how many of the donor cells are there?) and reported levels of 8-10%. However, they could not observe any dystrophin expression in the biopsy. Still authors maintain that stem cell transplantation was likely beneficial.
They do mention that more work is needed to fully elucidate the effect and outline the risk of stem cell transplantation (requiring the ablation of original blood stem cells – crucial for this patient due to his Diamond-Blackfan anemia, but a severe risk in regular Duchenne!)
Based on evidence provided here I am not at all convinced that stem cell transplantation helped to stabilize Duchenne in this patient. A number of comments:
- Duchenne was not genetically confirmed in this patient. Authors mention there was a history of Duchenne in the family. However, also no genetic diagnosis was done. Authors performed a dystrophin staining after the transplantation and saw reduced levels of dystrophin with the dys1 antibody (rod domain), and no staining with dys2 and dys 3 (C- and N-terminal). No pictures are shown of this! Only a picture of H&E staining is shown. So we cannot assess if the staining was done properly (e.g. laminin co-staining). No western blot is done either. Knowing that for sarcoglycanopathies dystrophin expression can be reduced, I would not want to rule out a different diagnosis.
More on why it is important to do genetic diagnosis for Duchenne. Regardless, based on the information provided here, we do not know for sure the patient had Duchenne or another muscle disease.
- Authors mention stem cell treatment is encouraging in mice. This is true but there are clear differences between mice and humans: mice are much smaller and have very good muscle quality due to efficient regeneration. Thus the stem cells have something to work with. In Duchenne the relative numbers of stem cells will be lower and muscle quality much worse, meaning stem cells will be vastly outnumbered and triggered by factors of the patient muscles to contribute to fibrosis or adipose formation rather than skeletal muscle repair (niche problem). It works in mice so it will work in human –> sadly not so
- Authors mention the patient is stable but they do not elaborate at all. All they mention is independent sitting for 3 hours. Nothing about muscle strength, respiratory function, arm function. This seems extremely arbitrary. Authors also do not provide natural history of other Duchenne patients – how long are they normally able to sit stably at this age? How much do they decline?
- The fact that CK levels are reduced does not mean the patient is doing better per se. Reduced amounts of muscle would also result in a drop in CK.
- The anemia and regular blood transfusions likely had a negative impact on Duchenne disease progression in this patient. Now that the anemia is ‘solved’ it is not surprising the patient trajectory is improved.
- A stem cell transplantation often results in a temporary improvement of Duchenne patients due to positive factors stem cells excrete. This is an approach Capricorn therapeutics is testing in trials – however this requires regular transfusions (every 3 months).
Long story short: based on this paper I have not changed my opinion on stem cell treatment for Duchenne (in the ‘non-Capricorn way’): there is currently no evidence whatsoever that this works. I know papers like this are used as evidence by those who offer stem cell ‘therapy’.
Hopefully my dissection illustrates there is no evidence: the patient may not even have Duchenne and ‘stability’ is an arbitrary opinion of the authors and not offset against natural history. For the ‘Capricorn way’ of stem cell treatment: trials are ongoing so no opinion there yet.