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Gene & Protein in Disease Gene therapy progress for DEB

Table 1. Examples of transgenic animals as models for DEB
Animal models DEB subtype Genetic/clinical features References
Gene-knockout mouse RDEB • Lack exons 46 – 69 of wild-type Col7a1 99
• Develop severe blistering of the skin and die 1 – 2 weeks after birth.
Hypomorphic mouse RDEB • Harbor an artificial gene-targeting cassette in intron 3 of Col7a1 100
• Reduce expression of type VII collagen (C7) to 10% of the normal level
• Present RDEB-like manifestations, including blistering, nail dystrophy, and mitten deformities
• Do not show the abnormal form and function of anchoring fibrils.
Tamoxifen-inducible RDEB • Harbor Cre-LoxP recombination sites that are induced by the administration of tamoxifen 102
Col7a1-knockout mouse to remove exon 2 of Col7a1, which creates a premature stop codon after 42 amino acids
• Lack of C7 in healing wounds
• Do not have chronic disease manifestations in the skin or other organs.
Transgenic DDEB mouse DDEB • Carry common human point mutations of p.G2034R and p.G2043R in COL7A1, and the 103
(patient-derived corresponding mutations in mouse Col7a1 are p.G2028R and p.G2037R
mutations) • Show micro-blistering and reduced C7 immunostaining
• C7 from these mice displays reduced thermal stability
• Do not have observable differences in growth and survival.
Transgenic RDEB RDEB • 5818delC homozygous mice had severe RDEB-like phenotypes and died immediately after 104
mouse (patient-derived birth.
mutations) • Adult E2857X homozygous mice showed hair abnormalities, syndactyly, and nail
dystrophy, and did not have a shortened lifespan compared to wild-type mice.
• c.5818delC/E2857X compound heterozygous mice presented an intermediate phenotype
between the c.5818delC and E2857X homozygous mice.
Abbreviations: DEB: Dystrophic epidermolysis bullosa; DDEB: Dominant dystrophic epidermolysis bullosa; RDEB: Recessive dystrophic epidermolysis
bullosa.

wounds with fibrosis and intact skin of DEB patients. In animal models for evaluating these treatments are critical
addition, topical administrations also need special drug steps in advancing therapeutic approaches. Despite the
formulations to avoid premature loss from the wound surface. challenges, significant progress has been made. The first
The first FDA-approved gene therapy for DEB treatment, gene replacement therapy has been approved and is now
B-VEC, combines an HSV-based biological suspension available to patients, marking a major milestone in the
into an excipient gel, which can then be directly applied treatment of DEB. However, gene editing therapies for
59
to wound areas. In clinical trials, B-VEC demonstrated an DEB have yet to advance to human clinical trials, with
approximately 40% increase in wound closure after 24 weeks, most strategies still under evaluation in preclinical settings.
highlighting the potential of this type of therapy. Promising early efficacy data from these studies highlight
Another administration option is intravenous the potential of gene editing strategies. To transition
injection, which can facilitate systemic gene therapy. So these advanced therapies from the laboratory to clinical
far, one systemic treatment has entered human trials, application, further improvements in the safety and
focused on administering recombinant C7 and stem efficacy of these treatments are essential. In conclusion,
cells (ClinicalTrials.gov Identifier: NCT05143190). there is an urgent need for the development of new and
Recruitment for this trial has now concluded, and the more effective gene therapies for all forms of DEB, with a
results are awaited. It is worthwhile to continue to invest particular focus on addressing the substantial unmet needs
effort in the further development and investigation of of RDEB patients.
alternative gene engineering strategies; however, systemic Acknowledgments
delivery of genetic materials poses a greater challenge for
delivery carriers, especially regarding safety. None.
5. Conclusion Funding
The extensive heterogeneity of mutations causing DEB This work was supported by the Chinese Government –
presents significant challenges in the development of China Scholarship Council (CSC202008300001), and
effective gene therapies. Designing precise gene therapy Science Foundation Ireland (SFI) Frontiers for the Future
strategies to target specific mutations and creating suitable 2019 call (19/FFP/6522).

Volume 3 Issue 3 (2024) 7 doi: 10.36922/gpd.4047