The Latest EB Treatment Strategies

Dr. Ping-Chen Hou & Dr. Chao-Kai Hsu (NCKU, Dermatology Department)

EB is caused by mutations in genes that encode structural proteins within the dermal-epidermal junction, leading to skin fragility and blistering. Treatments for EB have advanced for the past 30 years, which includes four major aspects: gene therapy, cell-based therapy, protein therapy and miscellaneous disease-modifying or symptom-relieving agents.

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• Gene therapy:

Gene therapies aim to correct the underlying genetic pathology. It includes two major aspects, gene replacement and gene editing therapies, and holds the promise to treat EB of any subtype.

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1. Gene replacement therapy: As EB patients are not able to produce functional protein due to the genetic defect, scientists utilize various ways, mostly viral transfection, to introduce a wild-type sequence of the mutated gene to the keratinocytes or fibroblasts, enabling them to re-express normal proteins. This therapy has been successfully applied to junctional and dystrophic EB patients, demonstrating good clinical responses. Of note, a German and Italian group made use of this method and successfully replaced almost the entire epidermis of a junctional EB patient. The patient can now play on the slides and run just like other teenagers.
    
2. Gene editing therapy: With the advancement of CRISPR/Cas9 by the 2020 Nobel prize winner, Emmanuelle Charpentier and Jennifer Doudna, and the recently emerging base editing technique, scientists can now modify almost any gene of interest. Although gene editing therapy is still at preclinical stage, it holds a great promise for not only control but able to cure the disease, especially when it combines with the iPSC (induced pluripotent stem cells) technique, invented by the 2012 Nobel prize winner Shinya Yamanaka. iPSCs are capable of differentiating into any lineage of cells as required. The combination of the two technologies serves as an important treatment resort in the future.

• Cell-based therapy:

Cell-based therapy is an umbrella term involving any sources of cells with treatment potential, including fibroblasts, mesenchymal stem cells, bone marrow transplant and so on. While this kind of therapy is predominantly used for recessive dystrophic EB.

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1. Fibroblast injections: Taking advantage of the allogeneic fibroblasts which are able to produce functional type VII collagen, scientists intradermally inject the fibroblasts from the healthy donors to replenish the production of the deficient protein to stabilize the skin.
    

2. Mesenchymal stem cell injections: There are various sources of mesenchymal stem cells, such as bone marrow, adipose tissue and umbilical cord. These stem cells are able to transdifferentiate into keratinocytes and fibroblasts to re-express the deficient proteins and also able to exert anti-inflammatory effects to better the chronic wounds and inflammatory status of recessive dystrophic EB patients. Previously, multiple groups have demonstrated improved wound healing after either intradermal or intravenous injections of mesenchymal stem cells from various tissue sources.
    

3. Bone marrow transplant: After successfully transplanting the bone marrow, part of the stem cells will migrate to the skin, producing sufficient functional proteins to reverse the disease phenotype. However, patients need to receive myeloablative chemotherapy and immunosuppressants ahead of the transplant in order to avoid rejections, which can lead to a considerable risk of morbidity and mortality, especially for EB, who has a relatively poor skin barrier.
    

4. Exosome: Recently, the exosomes are found to serve as a critical role contributing to the clinical efficacy of cell-based therapies. Therefore, cell-free therapy by merely inject the exosomes rather than the entire cell might emerge in the future.
    

• Protein therapy:

Since EB patients is in lack of a certain protein, an intuitive notion is that why don’t we just supplement them with that specific functional protein. This treatment strategy is now being used in recessive dystrophic EB. With the solid evidence from animal studies, the scientists are now launching a clinical trial investigating the safety and efficacy of intravenous recombinant type VII collagen infusions in recessive dystrophic EB patients.
 

• Miscellaneous disease-modifying and symptom-relieving agents:

Although the previous three types of therapies hold a good promise to control or even cure the disease, most of them are still in the stage of clinical trials and some can be expensive or hardly approachable. Thus, the scientists strive to investigate other on-the-market medications to improve the wound healing, itch or pain of the patients. These include dupilumab for EB pruriginosa, losartan for recessive dystrophic EB and so on.

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With the advancement of technology and the understanding of the pathomechanism underlying different forms of EB, we are now having more and more strategies to combat this debilitating disorder and improve patients’ quality of life.