In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial.
Irina GurevichPooja AgarwalPeiPei ZhangJohn A DoloritoStacie OliverHenry LiuNicholas ReitzeNikhil SarmaIsin Sinem BagciKunju SridharVisesha KakarlaVamsi K YenamandraMark O'MalleyMarco PriscoSara F TufaDouglas R KeeneAndrew P SouthSuma M KrishnanM Peter MarinkovichPublished in: Nature medicine (2022)
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.
Keyphrases
- wound healing
- herpes simplex virus
- clinical trial
- gene therapy
- phase iii
- poor prognosis
- patient reported
- double blind
- study protocol
- phase ii
- chronic pain
- endothelial cells
- placebo controlled
- gene expression
- radiation therapy
- stem cells
- genome wide
- squamous cell carcinoma
- open label
- binding protein
- magnetic resonance
- combination therapy
- dna methylation
- spinal cord
- neuropathic pain
- muscular dystrophy
- copy number
- adipose tissue
- metabolic syndrome