Advances in gene editing therapies offer hope for EB
New scientific publications from the EB House
Causative Therapies in Epidermolysis Bullosa
Epidermolysis Bullosa (EB) is a serious skin condition that can lead to life-threatening complications, including an increased risk of aggressive skin cancer. The most promising treatments aim to fix the genetic cause of EB by either replacing or repairing faulty genes or gene transcripts (RNA).
Researchers at the EB House have provided an overview of the current landscape of causal RNA and gene therapies for EB in two review articles. They emphasize the significant advancements in gene editing, particularly through CRISPR technology, which offers new hope for the treatment of EB. This technology enables precise corrections of harmful mutations and the removal of faulty gene segments. As the efficiency of CRISPR repair evolves, ensuring safety remains crucial to prevent unintended DNA alterations. Additionally, delivering gene editing tools to the skin remains a challenge, with two main approaches being explored:
- Ex vivo: This method involves correcting skin cells outside the body before transplanting them back. It allows for thorough testing of the cells before transplantation, enhancing safety. Studies on junctional EB (JEB) have shown that replacing the defective laminin gene can provide long-lasting benefits for patients, such as a significant improvement in skin stability. Currently, CRISPR is being adapted for this method to enable permanent correction with minimal side effects to key genes such as collagen 7 in dystrophic EB (DEB) and collagen 17 in junctional EB (JEB). However, long-term success also depends on correcting stem cells, which are hard to isolate. Induced pluripotent stem cells (iPSC) offer a promising solution as a renewable source of healthy cells for therapy.
- In vivo: This approach applies treatments directly to the skin, but targeting skin stem cells can be tough due to the skin’s protective barrier. In recessive DEB (RDEB), open wounds create a direct entry point for therapies. Vyjuvek®, an FDA-approved topical gene replacement therapy, uses a modified herpes virus to deliver the correct collagen 7 gene, leading to increased wound healing. This method requires lifelong repeated applications. Targeted repair of the faulty gene segments (e.g. with the help of CRISPR) in stem cells could prevent this, as the mutation is permanently corrected. Researchers are also investigating alternative viral and non-viral methods to deliver CRISPR tools into cells with minimal risk, thereby optimizing the effectiveness of future in vivo gene editing therapies.
Immunological Considerations
A challenge with gene therapies is the risk of immune reactions. The skin could attack newly produced proteins, especially in patients who cannot make them naturally. To lower this risk, current trials focus on patients who still produce small amounts of the protein. The immune system might also react to the viruses or tools used for gene editing, so more research is needed to improve safety.
Future Directions
Recent breakthroughs, like the approval of Vyjuvek®, and progress in gene editing treatments for other diseases, indicate that CRISPR-based therapies for EB are getting closer to clinical use. Alongside ongoing safety and efficiency concerns, regulatory challenges remain because each therapy is tailored to specific mutations. Thus, flexible methods are needed that can target various mutations, allowing more patients to benefit from these promising treatments.