Extraordinary epidermis regeneration in child via combo stem cell-gene therapy

Hirsch et al epidermal regeneration Fig. 2a
Hirsch et al., Fig. 2a

Epidermis regeneration is an important approach to helping patients with a variety of serious skin problems that can arise due to genetic conditions or injuries such as severe burns.

An exciting new Nature paper reports epidermis regeneration on a strikingly large-scale. The child who is the subject of the study suffers from a sometimes fatal genetic skin disease called junctional epidermolysis bullosa (JEB). In fact, in the particular case described in the new paper, the patient would have likely died without some transformative intervention given the severity of his JEB. Instead, after receiving a large combination transgenic skin graft, today he is doing well and has a largely normal epidermis. This encouraging outcome was reported in the paper by an international team (Italy and Germany) led by Michele De Luca entitled, “Regeneration of the entire human epidermis using transgenic stem cells.” Interestingly, this paper also points toward a central role for stem cells in epidermis regeneration and homeostasis.

The patient has a mutation in gene called LAMB3 that causes JEB so the core idea here was to replace the lost epidermis with new epidermis cells with wild type LAMB3 that would hopefully restore the patient’s healthy skin. The patient was in a dire situation after acutely losing 60% of his epidermis and having an overall ~80% loss. The team took a skin biopsy from a remaining relatively healthy area and used it to establish cell cultures, which were then transduced with a Moloney leukemia virus encoding a normal LAMB3 gene. They didn’t replace the mutant gene, but rather added a normal copy into the cells too to try to get some of the normal function back.

Transgenic epidermal sheets expressing the wild type gene were grafted onto the patient and remarkably the patient has had a near complete restoration of his epidermis as a result. This recovery was associated with restoration of largely normal LAMB3 gene expression (see part of Fig. 2a above). This is an exciting,  groundbreaking experiment combining cell and gene therapy for the skin in a way previously more often studied in hematopoietic disorders. The use of various versions of a combo gene and cell therapy could help thousands of other people. To be clear, there are going to be risks to this approach as well and perhaps even some negative outcomes, but especially in severe, likely fatal cases, the potential benefits make taking carefully considered risks justified within properly structured clinical experiments.

The very positive outcome of this patient so far is encouraging and some potential negative outcomes have not manifested up to this point. Such potential risks include cancer from viral integrations into functionally important genomic domains or some kind of toxicity from viral transduction or from enforced expression of LAMB3, but the team reports no such serious outcomes to date. Note that JEB itself is associated with an increased risk of skin cancer so monitoring will be important.

There are some interesting scientific findings in the study as well. This kind of therapy could potentially also have led to a dominate profile of a very limited number of the most successful cellular clones within the regenerating epidermis (in fact, I would have expected this to happen to some extent in certain skin regions), but it sounds like that didn’t happen. Hundreds of clones appear responsible for the new epidermal growth, rather than say just a handful of the most rapidly growing. Notably, on the other side of the coin if epidermal progenitor cells rather than stem cells had been responsible for the epidermal regeneration, based on genomic sequencing there would have likely been many thousands of independent clones in the boy’s regenerated epidermis, but there weren’t so this supports a stem cell-basis of regeneration here.

It’s possible over the coming years and decades that some regions of new epidermis in this patient could exhibit drift toward more limited clonal dominance so that should and likely will be monitored. Keep in mind that skin is very dynamic and turns over roughly monthly so things can and likely will change over time. It is also possible that this patient could have epidermal issues later if the new stem cell pool bearing the wild type gene becomes depleted over time or expression from the transgene fades or turns off. If that is observed, new skin grafts from the patient’s own banked corrected cells could potentially be utilized for subsequent epidermis regeneration.

It remains unclear what if any impact the gene therapy’s viral integration at many genomic loci including some at some genes could mean for the boy’s long-term health, but again results so far are encouraging. Even so, monitoring for potential skin-autonomous or indirect effects of this therapy on other organs will be important.

Overall, my initial take on this “N=1” study is that it was a major success so far that may catalyze other similar approaches to epidermis regeneration that could have big, positive impact for the regenerative medicine field and patients. There is reason for cautious optimism.

3 thoughts on “Extraordinary epidermis regeneration in child via combo stem cell-gene therapy”

  1. Hi Paul

    Glad to see you’ve stepped up to add your cautious optimism on the N=1 case report (actually more background in this pioneering area of skin based regenmed that should be refreshed). Hard not to take comfort in such efforts to save a child’s life – much like the early CHOP CART trial with Emily. Could be a watershed moment if it’s backed up with real community/industry support.

    Wrote a piece on The N Factor which is where more correctly weighted attention is warranted imo > http://msemporda.blogspot.com/2017/01/the-n-factor_3.html

    Keep up the glass half full spirit!


  2. Paul, this is a very interesting analysis of a very interesting intervention.
    Some questions spring to mind:
    (1) What would “properly structured clinical experiments” mean in this case? Would it be ethical to have the control group which doesn’t get the treatment?
    (2) Given the potential for side effects causing problems at some much later time: What might be the cost for both treatment and “proper” monitoring?
    (3) Would the genetic defect still be expressed in the patients germ cells? I suspect it would, which gives rise to a fourth question.
    (4) Is this an instance where, having intervened once, a stronger case could be made for using CRISPR technologies to prevent the disease (or other diseases associated with the treatment) from being passed onto any children of the patient?

    Skin is a pretty robust organ, as it has to be because it is the primary interface with a world full of hostiles. So, I’m not surprised at a positive result. Do you think that skin diseases might actually be a good place to invest a substantial amount of effort (as a model organ) for developing stem cell technologies?

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