Animal research brings hope to the girl whose skin never heals …

On Friday the BBC broadcast a moving report about a young girl named Sohana Collins, who suffers from the painful and life threatening genetic disorder epidermolysis bullosa (EB), caused by mutations in the type VII collagen gene (Col7a1). The report also included an interview with Prof John McGrath, Professor of Molecular dermatology at Kings College London, who is leading a clinical trial EBSTEM of mesenchymal stem cell therapy for EB that Sohana is part of, who spoke about the potential for this therapy to help people with EB.

Sohana Collins, who is participating in the EBSTEM trial. Image: BBC News

Type VII collagen (col7) is a key component of the basement membrane of the skin, a layer of protein structures that acts as a kind of cement that binds the outermost layer of the skin the epidermis to the underlying dermal layer, and lack of clo7 leads to the two layers to move independently of each other. This shearing movement at the dermal-epidermal junction hasthe result that even the slightest injury can lead to blisters and sores, and people with EB have a very high risk of developing skin cancers. The EBSTEMtrial seeks to determine if infused mesenchymal stem cells from healthy donors can migrate to the skin and produce col7, restoring the basement membrane and relieving the symptoms of EB. The clinical trial registration document for EBSTEM notes that evidence from both animal studies and (subsequent) small clinical studies indicates that mesenchymal stem cells have the potential to treat this condition.

So where does animal research fit in to this work? Well, as a 2012 review (1) by Prof. McGrath points out, genetically modified mouse models of EB have both provided key information on the role of col7 and how its absence leads to the lesions seen in EB, and also provide a system in which novel therapies can be evaluated.

A number of model systems have been developed to examine the pathomechanistic consequences of mutations in heritable skin diseases, and many of these systems are also being utilized for development of molecular therapies. Particularly valuable towards understanding of disease mechanisms has been the development of transgenic animal models which recapitulate the clinical features noted in patients; these genetically modified animals have played a major role in advancing our understanding of the disease mechanisms in different forms of EB (Bruckner-Tuderman et al., 2010; Natsuga et al, 2010). Besides providing direct evidence for the structural role of many of the basement membrane zone adhesion molecules, the development of transgenic mice with EB phenotypes has provided novel information on the complex secondary effects mediated by signaling pathways and other systems that modify the EB phenotypes. In addition to transgenic animals, EB phenotypes have been observed in a number of animal species, both domestic and wild, as a result of naturally occurring mutations (Jiang and Uitto, 2005; Bruckner-Tuderman et al., 2010). In many cases, the suitability of these animal models of human disease for preclinical testing of gene-, protein-, and cell-based molecular therapies has been documented.

A key early study was that of Professor John Wagner and colleagues at the University of Minnesota, who in 2008 reported that intravenous injection of wild-type bone marrow-derived cells could migrate to the skin lesions, produce the missing col7 protein, prevent blister formation, and extend survival in a genetically modified mouse model of EB (2), providing the first evidence that stem cell therapy might benefit people with EB. This study led Prof. Wagner and a team of researchers including Prof. McGrath to undertake a clinical trial of bone marrow transplantation in 6 EB patients, using standard chemoablative pre-conditioning procedures prior to transplant (which as we discussed in a recent post is quite a harsh procedure). The results were promising, new type col7 was noted in the basement membrane at the dermal-epidermal junction and clinical improvement was sustained for at least 1 year after bone marrow transplantation. However, two of the six children who completed the treatment died of complications of the procedure, that the risks of this kind of standard bone marrow transplant are too great in EB patients.

Subsequently another study in col7 deficient mice led by Dr Vitali Alexeev at Thomas Jefferson University indicated that when mesenchymal stem cells (a particular population of multipotent cells present in the bone marrow and other tissues that are being investigated as potential therapies for diseases such as multiple sclerosis) were transplanted into the skin they secreted col7, which was distributed throughout the treated area and formed connections with another collagen molecule col4 that necessary to restore the basement membrane (3). This study also demonstrated that the mesenchymal stem cells home in on areas of damage at the dermal-epidermal junction. This study combined with the earlier observation that bone marrow derived stem cells were injected intravenously in the GM mouse model of EB they ameliorated their condition provided good evidence that intravenous injection of mesenchymal stem cells may be a viable treatment for EB, and supporting decision to launch the EBSTEM trial.

A futher advantage of using mesenchymal stem cells is that while the EBSTEM trial is using bone-marrow derived mesenchymal stem cells, mesenchymal stem cells can potentially be obtained more easily from several other tissues, including fat tissue, which may provide a more abundant source of cells for transplant in the future. A drawback with intravenously injecting mesenchymal stem cells,compared to bone marrow transplantation, is that the benefits are less long lasting, and the procedure will need to be repeated every few months (the optimumfrequency required will be determined in later trials, but based on previous experience with MSCs it is likely to be about once every 6 months).

We wish Sohana and the other participants in this trial, and Professor McGrath and his colleagues, the very best of luck. While this new therapy is not a cure for EB, we hope that it will prove a major step towards that goal.

Paul Browne

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