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Gene & Protein in Disease Gene therapy progress for DEB

Figure 1. Palliative and potential therapeutic treatment for patients with dystrophic epidermolysis bullosa. Schematic created by the authors.
Abbreviations: DEB: Dystrophic epidermolysis bullosa; iPSCs: Induced pluripotent stem cells.

engineering approaches. These gene therapies aim to As ex vivo treatments, autologous keratinocyte cells were
manipulate COL7A1 at both mRNA and DNA levels and isolated from RDEB patients’ biopsies and transduced with
can be administered to patients either ex vivo or in vivo. a retrovirus carrying the full-length human COL7A1. The
Some clinical trials have utilized genetic strategies to transduced cells were used to make an epidermal sheet and
explore potential treatments for DEB. 47 grafted onto wound sites of 7 RDEB patients in a phase 1/2a
clinical trial (ClinicalTrials.gov Identifier: NCT01263379).
2.1. Gene replacement approaches Expression of C7 was maintained for 2 years in two
Gene replacement therapy shows significant promise participants in this trial. Alternatively, engineered
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for monogenic diseases and has demonstrated success fibroblasts have been used for intradermal injection as a
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in various heritable genetic disorders. The primary treatment for RDEB, 29,55,56 whereas Woodley et al. tried to
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obstacle in developing gene replacement therapy for DEB intravenously inject fibroblasts overexpressing C7.
lies in identifying a suitable gene delivery carrier capable COL7A1 gene delivery has been achieved directly
of encapsulating the large COL7A1 gene, which contains in vivo using viral carriers with improved safety (such as
8833 nucleotides encoding 2944 amino acids. self-inactivating lentiviral carriers and engineered herpes
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The first gene replacement therapy was reported by simplex virus [HSV] ), and polymer-based non-viral
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Chen et al. in 2000, in which a recombinant mini-C7 was carriers. 30,31,52 The direct gene delivery was carried out by
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produced with intact non-collagenous domains and part either intradermal injection or topical wound treatment.
of the central collagenous domain. The truncated 230 kDa The first U.S. Food and Drug Administration (FDA)-
mini-COL7A1 was encapsulated into a retroviral carrier approved therapeutic intervention for DEB, beremagene
and transduced into keratinocytes from RDEB patients geperpavec (B-VEC) developed by Krystal Biotech, is a
(RDEBK), and successfully reversed the cellular phenotype topical gene replacement therapy based on engineered
of RDEBK. Following this study, delivery of the full HSV. A phase 3 clinical trial of B-VEC (ClinicalTrials.gov
COL7A1 complementary DNA (cDNA) has been attempted Identifier: NCT04491604) enrolled 30 patients with RDEB
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using Ø31 bacteriophage integrase, new generation virus and one patient with dominant DEB (DDEB). Notably,
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carriers (lentivirus and retrovirus), 28,29,51 and non-viral approximately 70% of the wounds treated with B-VEC
carriers 30,52-54 in both keratinocytes and fibroblasts. achieved complete closure, whereas around 20% of wounds

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