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2015 EB Research Symposium

 2015 EB Research Symposium

This triennial meeting was held at the beginning of May in Atlanta. Forty presentations and three workshops involving 100 participants from all over the world spanned the 2½ day meeting. Thirty scientific posters were on display.

The meeting began with presentations and discussions on the clinical challenges in EB and patient perspectives with speakers including Jemma Mellerio (UK) and Dedee Murrell (Australia) focussing on issues related to quality of life and critically the design of clinical trials to ensure that the most appropriate outcome measures are selected.

The Epidermolysis Bullosa Research Consortium (EBCRC) was presented by Anna Bruckner (US). This is a group of North American Dermatologists with a common goal of facilitating collaborative research programmes that will lead to improving patient outcomes. Currently the focus is on anaemia and its impact in their patient cohort.

Martin Steinhoff (Ireland) presented his proposals for investigating itch in EB. This project is being funded by DEBRA UK and Ireland over the next three years and will concentrate on the key “pathways”, receptors and mediators in EB associated itch. The objective will be to develop a mechanism based subtype orientated itch treatment pathway.

Christina Gruber (Austria) and others presented data on antimicrobial peptides to improve wound healing, another core consideration in daily management. The impact of continued inflammation and alteration of the biome (microbiology) may also have important implications for skin cancer progression.

The session on genetics, genomics and diagnostics included some excellent presentations on advances in gene sequencing technology, identification of mutation patterns and specifically implications for cancer metastasis. There were excellent presentations on squamous cell carcinoma in EB from both Andrew South (US) and Cedric Gaggioli (France) both of whom we support in their research programmes.

The breadth and depth of development in treatment options covered a wide range of therapeutic approaches. Long term curative strategies have yet to be determined but gene, cellular and protein therapies are all under investigation. The optimal approach is likely to include an “outside-in” as well as an “inside-out” corrective methodology.

From a cellular perspective, John McGrath (UK) presented the most recent results of the EBSTEM study where donor mesenchymal stromal cells (MSCs) were infused into a small number of children with RDEB resulting in temporary qualitative improvements in health.

The next step in adult patients is to collect more quantitative data on how the cells behave after infusion and to determine the role they play. There remains a fundamental need however for an improvement in knowledge of the natural history of RDEB, the mode of action of these types of cellular therapy and the best way to test these innovative approaches. Joern Dengjel (Germany) presented work on the cellular environment in EB which may be valuable in understanding phenotypic (individual patient) variation.

A poster from F Palisson in Chile also provided positive results on two patients infused with MSCs. Taking the cellular therapy one step further, Katsuto Tamai (Japan) and his group have also had recent success with sub cutaneous transplantation of family donor bone marrow derived MSCs in severe RDEB patients. They are now looking to use the molecules or peptides involved when MSCs are used in this treatment setting, one of these molecules “HMGB1” has been identified as part of the healing cascade and will hopefully be taken into trials as a separate treatment.

Mitchell Cairo (US) presented an update on their advances, they plan to investigate if another type of “stem” cell - unrestricted somatic stem cells (USSCs) from umbilical cord blood will improve the outcome of children with RDEB at the next stage of their investigations.

Jakub Tolar (US) presented data on his growing cohort of patients undertaking bone marrow transplantation and amendments to both the conditioning regimen and treatment pathway leading to improved results.

Considering gene therapy and skin grafting, the challenge remains to select the best methodology for growing skin grafts – with keratinocytes or keratinocytes and fibroblasts (and transplant methodology) plus the optimal and safest method for gene correction (cutting/inserting or skipping faulty gene sequences).

 Alain Hovnanian (France) presented an update on GENEGRAFT, a joint French/UK initiative to develop gene corrected skin grafts (keratinocyte and fibroblast) for RDEB patients using a specific inactivated “viral vector” or carrier. The US groups including Peter Marinkovitch have already transplanted four RDEB patients within a phase I clinical trial setting, using alternative viral vector corrected keratinocytes. Angela Christiano (US) also presented advances in keratinocyte and fibroblast skin graft technology. Johann Bauer (Austria) has transplanted a patient with JEB and is now moving on with co-workers to plan further patient work. We know of course of successful transplants in the Netherlands in a patient with JEB revertant mosaicism and in Italy in conjunction with the Austrian group.

Fernando Larcher (Spain) provided an excellent update on the techniques for targeting nucleases – methodologies such as Zinc fingers, TALENs and CRISP/Cas9 and their roles in the advances associated with gene targeting and editing. All these are different ways of correcting the faulty gene sequences without using viral vectors, the names are all highly scientific but the methodologies are different ways of cutting and pasting. In his presentation Jakub Tolar specifically covered the potential for gene corrected corneal cells.

Other new methodologies for inserting corrected genes into cells include those presented by Wenxin Wang (Ireland) whose expertise in chemical engineering has provoked other technological developments with specially designed artificial polyplexes and the use of delivery mechanisms with a gene gun (EM Murauer, Austria).

Work is ongoing to accelerate the approval of inducible pluripotent cell (iPSC) based clinical trials in the US with Dennis Roop and his group. This strategy looks at taken the patients’ own cells and reprogramming them. The key will be to develop the most effective methods, although the field of regenerative medicine and stem cell biology is moving swiftly not only the US but in Europe with 3 presentations on iPSC work.

Skin delivery strategy is a further challenge with some new thoughts on micro needle techniques and the Acell® siRNA gene cream from Roger Kaspar (US).

Repurposing of drugs both for treatment and management is an up and coming area of opportunity as the academic world gains more access to suitable banks of agents for screening. Those presented at this meeting looked at amelioration of scarring, considering both the mechanism (David Woodley US) and treatment with Losartan [approved for hypertension] (Alexander Nystrom, Germany / Venugopal Mittapalli, Austria). One of the posters looked at the impact of Diacerein cream [approved for osteoarthritis] in EBS blistering.

Thomas Magin (Germany) presented key findings on the overlap between EBS and other inflammatory and immune disorders and strategies towards rational therapies.

Industry presentations included Fibrocell Science reporting on the development of genetically modified human dermal fibroblasts, following on from work previously done on fibroblast injections; Scioderm reporting on clinical trials for ZorblisaTM (wound healing cream) and Keraplast Technologies sharing results on KeragelT® (keratin gel) for treating hard to heal skin, reporting some clinical success.

Workshops on both cell banking and mouse model banking resulted in the agreement to share further knowledge between members of the scientific community, the potential for sharing existing cell lines and identification of opportunities for a central repository. This would help identify outstanding requirements and provide an opportunity to further characterise existing lines and provide quality control.

The pace of research is increasing with the next meeting confirmed two years from now – 2017 in Salzburg, Austria. 

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