Big laminin paper: Gene therapy for junctional epidermolysis bullosa

When I started this blog I envisaged it as a way to acknowledge lab achievements and celebrate the successes of the Hamill lab team members. As we have gone on it has developed and changed (and I would like to think got better) and its time for the next evolution; “Big laminin papers” (wondering what a laminin is? See the video at the bottom of the page)

First up is a laminin story that made it to the mainstream media as the implications are pretty huge! A case report describing a junctional epidermolysis bullosa patient  receiving effective treatment for their debilitating disase. Bit strange, picking a case report? Well the treatment is pretty awesome; skin transplant of ex vivo repaired cells to effectively cure someone who had no other treatment options left and would have died soon. Original article in Nature by Hirsch et al from Michele De Luca’s group available here (paywall).

Paper choice

In many ways picking a translational science paper for the first “big laminin paper” feels a bit strange. So far this year there have been over 100 papers with “laminin” in the title including some thoroughly impressive papers that are much closer to what my lab work on (eg important potential therapy for muscular dystrophy based on laminin polymerisation from Peter Yurchenco’s group, a comprehensive investigation of netrin-4 effects on laminin matrixes, crystal structures from the Hohenester group, and  useful papers using laminins to improve culture conditions for stem cells including for limbal epithelial stem cells and pericytes that we grow), any or indeed all of which are worth commenting on and are directly relevant to what we are doing. However, this one touched me in a different way.

Junctional epidermolysis bullosa (JEB) is a rare but truly horrible disease. Patients present with  horrendous all over blistering in response to really mild mechanical trauma; indeed, they get referred to as “butterfly children” as their skin is as fragile as a butterfly’s wing. You can read more about it at DEBRA: the charity dedicated to researching the disease and therapeutic interventions to treat and hopefully, ultimately cure, the disease (or technically diseases). JEB itself is rare but there are a variety of other variations in the epidermolysis spectrum that mean the overall incidence is about 5000 people in the UK, 1/17000 births.

Electron micrographs of the hemidesmosomes in normal skin (left); often described as “spot welds” their job is to button down the epidermis onto the underlying stromal tissue. On the right you can see what happens in epidermolysis bullosa, where the split in the middle results from a failure to assemble this structure.

As most the people who are reading this will probably be aware (as I have no doubt told you about laminins at some point whether you wanted to hear or not!). I have been directly and indirectly working on projects related to JEB and the proteins involved for the past 15 years. Indeed my first postdoctoral position was supported by DEBRA so its always been a subject that is close to my heart. Indeed my first real contribution to a paper and  a chapter in my doctoral thesis was dedicated to identifying the mutation that causes a rare form of JEB.

What makes this paper such a big deal?

In this paper, the authors treated a patient who had lost 80% of their skin to the blistering and sloughing off the skin that results from the weakness in the junction between the epidermal layers and the stroma. If you think how painful one blister is, can you imagine how bad losing the skin on most of your body is? Indeed, here, the disease was so bad that the treatments were essentially limited palliative.

Laryngo-onycho-cutaneous syndrome; a variant of JEB where patients overproduce granulation tissue. This disease was the starting point for my PhD and my entry into the world of laminins!

So, what they did was take a biopsy from a region of non-blistered skin, grew up the cells in culture and used a retrovirus to correct the mutation in the laminin beta 3 gene. They then expanded the cells in culture and grafted the repaired cells back onto the patient. Lots and lots more rounds of treatments, more grafts and more cells, and 2+ years later the boy they treated has essentially normal skin. Safe to touch, to the extent his parents are now even able to hug their 7 year old for the first time.

It should be noted that smaller grafts with longer follow up have been done before, indeed Prof De Luca’s group reported the approach in Nature Medicine in 2006. However, the difference now is the scale. This is the real proof that this approach is viable for patients who otherwise at best case would be in for a life of pain.

Importantly, it proves concept; gene correction and grafting can be done even in really bad cases and it actually provides hope for patients living with some of the multitude of other diseases where gene correction could be the answer.

Its not all good

The stories in the news carry the excitement but there are some issues.

The gene editing process itself introduces a whole bunch of additional genetic changes, the practical upshot of which is that there is a real potential that some of those mutations can lead to additional, different problems, most obviously cancer. As you would expect, the incidence and pathways in which genetic changes occurred in this patient were mapped in order to determine how big a problem this is. These data showed that were indeed many including  mutations in coding regions of numerous genes (though apparently not in the key cancer pathways). However, 2 years out, the patient has no sign of cancer in any of his new skin and his quality of life has improved enormously.

Another point to note; although more than 40% of patients with JEB die in childhood, if they survive to adulthood, they have much higher incidence of skin cancers than the general public so am increased* cancer risk isn’t something that would put patients off.

*possibly increased; this is a fear rather than proven increased risk at this point.

Another current limitation is that its only the surface epithelium that was treated. With this disease other epithelium eg the linings of the wind pipe and GI tract are affected. Often these aspects of this disease are more manageable but the patient will still require extensive medical care.

Bench to bedside. It’s a journey.

Why I really chose to highlight this paper is because, even though it is an endpoint paper, it effectively highlights the importance and massive value fundamental research has. To be clear, when I read this type of research, while I appreciate the vital work the clinicians who delivered the final therapy have done, I read it with the understanding that it marks an important step within a long journey that was absolutely dependent on lab based research.

In no uncertain terms, this treatment could not have been achieved without the seminal work identifying the pathogenic mutations more than 20 years ago, and indeed the work that started 10 years before, that identified the hemidesmosome  (that my postdoctoral mentor Jonathan Jones was massively important in this), and ultimately their protein constituents that helped direct the search for the mutation. This current development also required more recent discoveries that identified the strategies to edit the genome and the subsequent hard graft needed to optimise the approach so that you could make the change you want without massive other problems. It also took the identification, isolation and expansion of stem cells in culture and development of scaffolds upon which to expand epithelial sheets to allow grafting. So while this paper is indeed huge and worthy of press attention (and hopefully increased donations to DEBRA that will come from it), it is not just the authors that should be feeling proud but also all the scientists that allowed the treatment to get to this stage. The preceding research may not have made it onto the BBC but it’s no less sexy in grand scheme of things.

Keep on researching!

People sometimes describe fundamental research as “basic” science but none of this stuff is or was basic. Without “discovery” science (a much more appropriate term) the science that underpins the next big therapy will never get developed. Developments like these that reflect more than just an incremental advance, that took hundreds of groups working over many decades, require and are worth the investment in time and effort that they take.

To students on a discovery track, this work also shows that you don’t have to work on a project that is translatable tomorrow for it to be worthwhile. Indeed, the most worthwhile research might take longer than the extent of your current project.

A final point

This treatment doesn’t mean the story is over. Lots more work is required before other patients can benefit and this treatment will not necessarily work for all types of EB. Indeed, even for people with the same exact mutation this therapy may not work if the disease has progressed so far that the underlying stroma is so damaged that grafts are no longer possible. So, if you want to help support a charity that not only works tirelessly toward supporting patients with the disease but also are committed to supporting the discovery science needed to provide a cure for all, you can do so here; DEBRA.


Introduction to laminins

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