One of my personal highlights from this year’s Till and McCulloch Meetings was attending the “Science for Citizens” panel (reported on in a previous post). Experts including Timothy Caulfield, patient advocate William Brock, and National Post writer Tom Blackwell emphasized the dangers of “fake news” in science and health care. I left that panel determined never to write an over-hyped headline again.
I realized that I had fallen off the wagon when I sat down to write this blog post about a recent report in Nature, and titled it “New Therapy Regrows Skin of Critically Ill Patient.” Sounds like something out of the National Inquirer, right?
I was intrigued by this paper because of the high-quality science and potential impact. In this post, I hope to share some of my excitement about this study, and explain the significance of the advancement without going too “National Inquirer” on you. Mr. Caulfield, Mr. Blackwell, Mr. Brock, maybe you’ll tell me how I did?
A group of scientists, led by a veteran researcher in cell and gene therapy – Dr. Michele De Luca – has regenerated the entire skin surface area of a patient with a genetic disease that results in severe blistering. Epidermolysis bullosa (EB) is a rare disorder that affects one out of every 20,000 births in the U.S. every year. This serious, and potentially fatal, condition results from genetic mutations in genes that code for laminin – a protein that is an important component of the foundation layer of the skin known as the basement membrane. For EB patients – sometimes called butterfly children due to the fragility of their skin – the slightest mechanical stress (a pinch or a tug) can cause skin blisters that often grow into large, chronic wounds. Skin lesions leave EB patients at risk of infection and predisposed to skin cancer. There is no cure for EB and just under half of all patients die before reaching adolescence. (This may be familiar to readers of Signals as we’ve blogged about EB and Canada’s “butterfly boy” here.)
This study is interesting because it provides a paradigm for treating a serious condition, while at the same time capturing important mechanistic information about the biological processes that underpin the repair they are seeing with this approach.
The researchers used a technique known as ex-vivo gene therapy – where genes are modified in cells or tissues outside of the body. More specifically, their approach was to take a skin sample from a critically ill EB patient and correct mutations in laminin coding genes in those cells. Large numbers of gene corrected skin cells were grown in culture and then used to generate skin grafts that were transplanted onto the patient in a series of operations.
At the time of treatment, the patient had complete skin loss on over 80 per cent of the body. Almost two years after treatment, gene edited grafts had restored all lost skin and the patient was no longer experiencing blistering. A major achievement, especially for this crucially ill patient who was on the brink of palliative care prior to receiving this treatment.
Exciting, right?! But let’s do a “hype check” and look at the big picture.
First, a note on the clinical trial design: this is a single patient case study.
Testing this therapy on only one patient is by no means a drawback of the trial. In rare diseases, it is typical for early phase clinical trials to be performed on single subjects due to the limited patient population. However, it is important to note that later phase trials, with more patients, would be required for this therapy to obtain regulatory approval, and eventually reach the market.
Further, the authors acknowledge that the dramatic results were due in part to the patient being very sick to begin with. An aggressive treatment was used because it was the patient’s only option. In cases where the disease is not as severe, such a radical approach would not usually be taken. Finally, this treatment is not a complete fix for these patients who also suffer from blistering – albeit less serious – of the internal mucosae (mucous membrane).
The real impact of this study is that it will provide a roadmap for similar approaches that could be used more widely. In fact, the authors do a great job of communicating this in their paper.
A reason to be optimistic that the findings of this study will have positive impact for patients is that they are backed up with strong mechanistic data.
Important biological insights came from comparing the stem cell populations in the original cultures used to generate skin grafts, and in cultures of cells obtained from engrafted skin almost two years post-transplant. Remember, the cells that were originally harvested from the patient — including a population of stem cells — underwent gene correction to repair laminin mutations. Every gene corrected cell effectively carries a genetic marker and can be identified with genome sequencing tools.
Using this approach, researchers determined that a small population of self-renewing stem cells, which persist in grafted tissues, are responsible for the majority of skin regeneration.
This important observation provides novel evidence that cultured, skin-derived stem cells can survive, engraft and retain their ability to self-renew following transplantation. Further, it gives researches a practical understanding of the number of stem cells that should be present in a skin graft to achieve successful skin regeneration. Finally, this observation provides important indications about the safety of using gene therapy to repair genetic mutations in skin cells.
Any gene therapy comes with the risk of unwanted genetic changes, which can, in some cases, lead to cancer. If a small population of gene corrected cells is giving rise to a larger population of descendants, those descendants will carry a restricted set of genetic changes, reducing the chances that an off-target alteration can have an adverse effect.
No need for an over-hyped headline here. The science speaks for itself.
Latest posts by Nicole Forgione (see all)
- Second skin: A regenerative medicine approach to treating genetic skin diseases - December 5, 2017
- RMConnectTO: Building networks to advance regenerative medicine - October 12, 2017
- Learning About Industry from the Insiders at Phacilitate Cell and Gene Therapy World 2017 - February 8, 2017