Hirsch et al., Fig. 2a

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

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

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

The patient has a mutation within gene called  LAMB3 that  leads to JEB s o the primary idea here was to replace the lost epidermis along with new epidermis cells with wild type  LAMB3   that would hopefully restore the patient’ h healthy skin. The patient was in a dire situation right after acutely losing 60% of his epidermis and getting an overall ~80% loss. The team took an epidermis biopsy from a remaining relatively healthy area and tried 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 as well to try to get some of the normal function back.

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

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

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

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

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

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

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