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What would an EB cure look like?


It is likely that eventual cures will combine various approaches currently in development, with novel technologies and therapeutic concepts as yet to emerge from fundamental research into EB.

Because EB is caused by a fault in a gene, which in turn produces a faulty skin protein, a cure for EB must either,

  • supply the correct gene able to make the missing protein (gene therapy)
  • supply the missing protein (protein therapy)
  • supply cells carrying the correct gene (cell therapy)
  • remove the faulty protein, and/or provide alternative compensatory proteins, or modify the skin microenvironment (siRNA or small-molecule drugs)

so that the skin can be assembled and function correctly.

Ideally, a therapy for EB would be a safe, once-only, systemic (whole-body) treatment that resulted in a lifetime cure. Such a therapy is still some way off, although emerging therapies for EB include gene-, protein-, cell- and drug-therapies.


Gene therapy


Gene therapy aims to correct the genetic defect by grafting sheets of cells containing the corrected gene. It is important to get the genes into skin stem cells, the cells with the ability to reproduce indefinitely.

A major challenge in gene therapy is whole-body delivery of the therapeutic gene: large-scale grafting and internal sites are a problem.

In Europe, a research consortium is developing gene therapy for severe RDEB (GENEGRAFT project). In the USA, a gene therapy trial for severe RDEB is undertaken at Stanford University.


Protein therapy


Protein therapies involve injecting whichever protein is deficient into the patient. The human protein is made in the laboratory, synthesised from the human gene which has been cloned.

Early work injecting collagen protein directly into wounds shows good wound healing.

Although protein therapies offer only temporary treatment, and patients will require repeat treatments for life, they offer the possibility of a likely relatively safe treatment that improves wound healing.

Late preclinical research, or early-stage clinical trials of protein therapy for RDEB are in development at several academic and clinical centres, and at a biopharma company, and earlier stage research is investigating the possibility of protein therapy for JEB.


Cell therapy


Cell therapies involve injecting genetically correct cells from a donor, or the patients' own stem cells after genetic correction, back into the body.

Local cell therapy


Injection of donor fibroblast skin cells directly into the skin can improve wound healing, reduce blistering and strengthen the skin. The benefits are limited to the areas injected.

Although the improvements will be temporary, and therefore repeat treatment is required, the benefits can last for several months to more than a year.

Phase II trials of a fibroblast therapy for treating DEB are underway (2011) as a collaboration between Kings College London, Guys and St Thomas' Hospital and a small biopharma company.

Systemic cell therapy


Systemic cell therapies will correct cells at all affected sites in the body: stem-cell therapies (e.g. bone-marrow stem cells from a donor, mesenchymal stem cells or, in the future, induced pluripotent stem cells) are possible therapies currently in development.

Bone-marrow stem cells - Bone marrow transplant therapy is a type of stem-cell therapy, in that it provides the treated patient with a new supply of genetically correct stem cells from the bone marrow of a healthy donor. The faulty cells in the bone marrow of the patient must first be destroyed by chemotherapy: cells from the donated bone marrow then replace the faulty cells in the bone marrow of the patient and eventually are able to produce healthy new cells of various body tissues.

The early results of the first-ever clinical trial of bone-marrow transplantation (BMT) to treat RDEB have been published. BMT is a severe medical procedure, not to be undertaken without serious consideration of the possible consequences. However, this trial appears to indicate that bone-marrow transplant – or, in future, related therapies – may, in principle, provide benefits to some patients with severe RDEB.

Two clinical trials of bone-marrow transplants from healthy donors without EB into children with severe RDEB are currently ongoing in the USA, at both University of Minnesota, and Columbia University Medical Center, NY. Early results from the Minnesota trial indicate that, in some patients, there may be some benefit derived from bone marrow transplants. However, it is not yet known exactly how the bone-marrow benefits the patients, nor whether the benefits will be long-term.

Mesenchymal stem cells (MSC) - Bone marrow has long been known to produce stem cells, including MSC, that can help to repair body tissues, hence the use of bone-marrow transplants in medicine. MSC are already being used to supplement bone-marrow transplants for severe EB.MSC are a type of stem cell that can differentiate into cell types in a wide variety of tissues, including bone, fat and skin. When transplanted by injection into the bloodstream, MSC migrate to the site of injury. This has been shown in animal models for EB and underpins the hope that they will be useful to develop cures for EB.Anecdotal reports of MSC use to treat individual EB patients by injection of MSC, both local (into skin around wounds) and systemic (in the bloodstream to treat the whole body), report some benefits and limited side effects. An understanding of the natural biological role of MSC in body repair also indicates that they are good candidates for EB cell therapy. It is now important to follow up results to date with systematic, methodical studies to establish the parameters for safe and effective use of MSC therapies.

Several leading laboratories worldwide are engaged in late preclinical research, or early-stage clinical trials developing mesenchymal stem cell therapies.

Induced pluripotent stem cells (iPSC) - These are cells which resemble but are not the same as embryonic stem cells in that they are capable of developing into most types of body tissue.

iPSC are produced in the laboratory from adult tissue cells (e.g. skin cells) by reversing the process by which they originally developed from embryonic stem cells. iPSC can be produced using any of several different techniques which are still being refined to improve the safety and therapeutic usefulness of iPSC.

The advantage of iPSC is that a new supply of stem cells for therapeutic purposes can be developed from a patient's own tissue, so avoiding any of the problems of transplantation from a donor.

DEBRA International is funding research at IMBA (Austria) to develop iPSC for JEB and RDEB, and at the University of Colorado School of Medicine to develop iPSC for EBS. CIRM (California Institute for Regenerative Medicine), in collaboration with the UK MRC (Medical Research Council) and Canada's Cancer Stem Cell Consortium has granted $11.7M to a worldleading EB research team in Stanford University to develop iPSC (induced pluripotent stem cell) therapy for dominant dystrophic EB (DDEB).