Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genetic skin disorder that leads to severe blistering, wounds, scarring, and usually an untimely death. Up to now it has had no approved specific therapies at all, so its victims have basically been left to suffer. This disease has had a quite a run preying on genetically unlucky people.
But — thanks to a long history of dedicated researchers working towards viable gene therapies — if you’re RDEB, suddenly your future isn’t looking too bright. A gene-therapy gel (!) that can be received in the mail and used at home causes skin cells to make their own functional collagen VII, the missing component in RDEB. Great clinical improvements are already being reported in Phase 1 and 2 human trials. Check it out in a March 28 report (open access) in Nature Medicine.
If looking at skin wounds makes you squeamish, don’t scroll all the way to the end. I’ll stop you just before you get there — but then you’ll miss the awesome results!
So first we have to appreciate what collagen VII does for us: it plays a big part in holding the main layers of the skin — the dermis and epidermis — together. People with defective collagen VII get blisters and skin breakage really easily because these two layers don’t adhere very well.
You can see in the simplified figure below how collagen VII fits in. Down in the dermis, you have big, thick fibrils (shown in pink) made up of collagens I and III, and looping around those is the ropelike collagen VII (shown in gold). Collagen VII also attaches to other proteins up toward the epidermis and thus is a big part of the reason the two layers can stay together despite some bumps and scrapes.
Not only does collagen VII loop around the thick collagen I/III fibrils in the dermis, it actually sticks to them pretty tightly. If you mechanically pull apart a section of skin and look closely at the collagen I/III fibrils, you will find pieces of collagen VII stubbornly stuck to them. That’s what was done for the picture below, where the bits of collagen VII stuck to the fibril are shown by white arrows. The black dots are gold particles that stick only to collagen VII because they’ve been coated with the appropriate antibodies.
You can see in the main title picture above that collagen VII hangs out very specifically between the dermis and the epidermis, so let’s zoom out to clearly show those layers in context. I like this diagram not just for all the weird stuff lurking beneath the surface of your skin (who knew?) but also because it actually shows the epidermis detaching from the dermis, which is exactly what can happen when collagen VII is defective.
Most of us can take our 20 square feet or so of skin for granted. But you can imagine how difficult things are going to be for you if your skin pulls apart easily like this because your collagen VII can’t play its part in holding the layers together.
Fortunately we know exactly what a normal collagen VII protein looks like, and we can easily make a gene that will give the instructions to produce it. The trick is how to safely and effectively get that gene into your skin cells so that not only do you make enough collagen VII protein, but also so that we don’t trigger a severe immune response or screw up other genes and cause a tumor. Simply applying DNA to the skin has been tried for this, but it doesn’t work.
This is where our newfound friend, the herpes virus, comes in.
Herpes! It would be good if Tim Kazurinsky could be here to support me with some placards:
Then again, a spoof “medical” video might trigger certain people to drive their trucks around in circles for three weeks or try to kidnap governors, so let’s just leave it at that and move on….
It turns out that the herpes simplex virus type 1 (HSV-1) — the cold-sores kind, not the genital kind — is a terrific vehicle for getting DNA into cells, for the same reasons that it’s such an effective virus. It infects cells really well, and it’s so good at evading the immune system that there are still no effective vaccines against it.
The HSV-1 that’s been engineered for therapy has its replication and pro-inflammatory genes removed, so we’re left with a nice gene-delivery vehicle (now with room for extra genes!) that simply does its job and then retires without lasting effects. The other good thing about HSV-1 is that you can pack a lot of DNA into it, much more so than other common viruses that are used for gene delivery. The collagen VII gene just so happens to be pretty big, so this is a great fit.
Not only that, but HSV-1 DNA doesn’t integrate into your chromosomes like some other viruses, so it can’t insert DNA somewhere that triggers cancer or other genetic disorders.
You know, I’m actually kind of liking herpes now! (Good thing I’m not dictating this over the phone as someone walks by.)
Now let’s take a look at some real results. Don’t scroll down any more if you don’t want to look at skin wounds. You’ll have to trust me that some fabulous things happen.
Below are RDEB wounds treated with the gene-therapy gel or a placebo gel, at the beginning of the trial vs. 3 months afterward. These aren’t all of them, but I pulled a panel of three patients (p9, p10, and p11) whose pictures I could line up easily just to show you some typical outcomes. And the wounds will also illustrate just how tough this disease is.
Each patient had two wounds treated with the gene-therapy gel (at left) and one similar wound treated with a placebo gel (at right). Not much going on with the placebo, but the treated wounds are all practically gone. Look at how the skin regenerated and closed up these wounds:
Wow, unbelievable! There weren’t any notable adverse effects in any of the patients, either. It looks like nasty old RDEB has finally begun its swan song. For people who get this treatment, it’s going to be life-changing, the difference between doing things and not doing things, plain and simple. It surely will mean a longer life as well.
There’s a startup company in Pittsburgh (in which I have no financial or other interest whatsoever!) developing the therapy, which is now in Phase 3 trials. If you’ve lived in Pittsburgh at any time over the past, oh, 48 years, you’ll especially appreciate it when I say that at this point RDEB doesn’t know whether to cry or wind its watch. We’re beating it like a rented mule, and we’ll be smilin’ like a butcher’s dog when we’re able to say that RDEB has just … left the building.
Even with the decades-long bumpy road it has been on, gene therapy (now including gene editing) is still just emerging, but we’re starting to see successes like this that are helping us learn the rules, and we’re gaining momentum. Some would even say we’re at an “inflection point”.
But as for right now: RDEB sufferers, here’s hoping that much better days are at hand. And that from here on out, your dermis and epidermis will always be together…..