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Advancements in gene therapy for epidermolysis bullosa

Presented by
Dr Peter van den Akker, University Medical Center Groningen, the Netherlands
DDD 2024
Gene therapy is an exciting field in medicine, and novel options have been emerging for patients with epidermolysis bullosa (EB). Dr Peter van den Akker (University Medical Center Groningen, the Netherlands) provided an overview of the latest advancements and their clinical implications.

EB is a blistering disorder caused by a non-functional type 7 collagen. “The production of type 7 collagen starts with a piece of DNA, which is transcribed into an RNA copy, and then translated into the protein type 7 collagen,” explained Dr van den Akker [1]. “Individuals inherit 2 copies of genes, 1 from the mother’s side and 1 from the father’s side. If both copies are mutated, the RNA will not be translated into functional type 7 collagen.” This is what occurs in patients with recessive dystrophic EB. “What options do we have to restore the type 7 collagen production?” asked Dr van den Akker.
Potential of CRISPR-Cas9 in gene correction

Interventions can occur at various levels, ranging from DNA therapy, such as genome editing, to RNA therapy, including splice modification and RNA editing, as well as protein therapy and cell therapy.

“Genome editing through CRISPR-Cas9 would be the holy grail for correcting DNA mutations throughout the body,” expressed Dr van den Akker. “CRISPR-Cas9 can be used either to remove the mutated gene or add a corrected DNA template.” These options are being investigated in patients with EB but have not yet been tested in vivo. If these interventions are successful, an individual could potentially be permanently treated with a single treatment. However, it is still unknown whether it is safe and how to control for off- target effects. Moreover, it is a highly personalised therapy and requires much effort to develop for a single person.
Gene addition and replacement therapies

Dr van den Akker also focussed on gene addition/replacement therapy, which is not a corrective technique like CRISPR- Cas9 but adds a working copy of a gene into the cells. Gene addition/replacement therapy has been successfully utilised in a patient with junctional EB, and the long-term effects show that the transplanted skin was still intact after 5 years of follow-up whereas the untreated skin displayed symptoms of junctional EB [2,3].

“This is actually a combination of DNA therapy and cell therapy,” commented Dr van den Akker. This therapy is permanent in the treated locations and can be easily controlled for off-target effects. However, it does not include treatment of internal organs or mucosa and comes with a heavy treatment burden for the patient. “Not many patients with EB are fit enough to endure the many surgical procedures needed to complete this therapy,” added Dr van den Akker.

Recently, the FDA approved an in vivo gene addition/ replacement therapy called beremagene geperpavec for wound treatment in patients with dystrophic EB. The producers used an inactivated herpes simplex virus and added a working copy of the collagen 7 gene. Beremagene geperpavec was tested against a placebo in participants with dystrophic EB in a phase 3 study [4].

After 6 months, complete wound healing occurred in 67% of the participants on beremagene geperpavec and 22% of the participants on placebo, reaching a statistically significant difference. “Although this is an easy-to-use gene therapy that successfully heals wounds in patients with EB, its effect is temporary, and we do not know yet what the immune response will be in the long term,” commented Dr van den Akker. “Also, this therapy may cost up to 30 million dollars per person over lifetime” [5].
Oleogel-S10: An immunomodulatory approach for dystrophic EB

Then, there is oleogel-S10, an immunomodulator made from birch bark extract (10%) and sunflower oil (90%), which can be applied to wounds in patients with dystrophic EB. “This agent will not help you to produce more type 7 collagen,” argued Dr van den Akker. “So how does it work?” It is hypothesised that it influences inflammation, the differentiation of keratinocytes, and the renewal of tissue [6,7]. The therapy is approved by the FDA and EMA. However, long-term effects are unknown, and the underlying pathomechanism is not fully understood. Furthermore, the price is also high, according to Dr van den Akker.
Exon skipping techniques for recessive dystrophic EB

Finally, Dr van den Akker discussed exon skipping as a therapy for recessive dystrophic EB. This RNA therapy involves manipulating pre-mRNA during the splicing phase. Synthetic RNA is added to the mutated exon. Consequently, the mutated exon is no longer recognised as an exon. Thus, the mature mRNA will not contain the mutated exon. The shorter mRNA can still be translated into a functional type 7 collagen protein. A mouse study suggests this technique may work as a systemic therapy in recessive dystrophic EB [8].

“We are conducting ex vivo studies in Groningen, which have delivered promising preliminary results as well,” added Dr van den Akker. The big advantage is that this is a potential systemic therapy that also reaches internal organs and mucosa. On the downside, this is not a permanent therapy, it is not yet established how to reach target cells, and it may come at a high financial cost.

  1. Van den Akker P. Gentherapie bij epidermolysis bullosa. Dermatologendagen 2024, 11–12 April, Amsterdam, the Netherlands.
  2. Hirsch T, et al. Nature. 2017;551(7680):327-332.
  3. Kueckelhaus M, et al. N Engl J Med 2021;385:2264-2270.
  4. Guide SV, et al. N Engl J Med 2022;387:2211-2219.
  5. Raymakers AJN, et al. JAMA Dermatol. 2024;160(3):297-302.
  6. Schwieger-Briel A, et al. Dermatol Ther. 2019;32(4):e12983.
  7. Kern JS, et al. Br J Dermatol. 2023;188(1):12-21.
  8. Bremer J, et al. Mol Ther Nuc Acids. 2019;18:465-475.

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