In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain–severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.

New developments in the molecular treatment of ichthyosis: review of the literature

“…Investigation of topical gene therapy has also been done by Gurevich et al . [ 104 ] for recessive dystrophic epidermolysis bullosa (RDEB), which is caused by mutations in the COL7A1 gene that normally encodes for collagen VII (C7). They investigated beremagene geperpavec (B-VEC), a replication defective HSV-1 vector containing two copies of the COL7A1 coding sequence .…”

“…The results of Gurevich et al . [ 104 ] regarding B-VEC for RDEB patients as described above, were further investigated in a phase I/II trial. In this trial, nine RDEB patients received B-VEC treatment.…”

Enhancing Stem Cell-Based Therapeutic Potential by Combining Various Bioengineering Technologies

“…In addition, epidermolysis bullosa (EB) is a severe skin disease associated with skin fragility, which is caused by different genetic mutations of some genes involved in regulating adhesion of basal epidermal cells to the underlying basement membrane ( Jackson et al, 2017 ; Alharthi et al, 2021 ). Therefore, gene therapeutic strategies linked to EB can be applied to induce tissue regeneration of EB skin lesions or prevent EB-indued wound healing abnormalities ( Marinkovich and Tang, 2019 ; Gurevich et al, 2022 ). In this context, eenetically modified skin-derived stem cells have great potential as successful cell-based gene delivery systems locally or systemically.…”

Revertant Mosaicism in Genodermatoses: Natural Gene Therapy Right before Your Eyes

“…Most approaches under study for EB therefore focus on topical treatment [ 109 ], either by topical compound delivery (e.g., in vivo gene-addition by viral [ 110 ] or minicircle non-viral vectors [ 111 ], antisense oligonucleotides [ 112 ]), ex vivo gene-replacement or gene-correction followed by injection of corrected fibroblasts [ 113 ], or the transplantation of large epidermal sheets cultured from ex vivo -corrected keratinocytes [ 114 , 115 , 116 , 117 ], analogous to the treatment of full-thickness burn-wounds [ 118 ]. In 2017, Hirsch et al reported a 7-year-old boy with laminin 332-deficient JEB in whom almost the entire epidermis (~0.85 m 2 ) was replaced using exogenously corrected, autologous skin grafts [ 119 , 120 ].…”