Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, life-threatening bullous genodermatosis (1, 2). Genetic mutations in the COL7A1 gene lead to lack of functional type VII collagen (C7), a large triple-helical protein found beneath the lamina densa (2-4). C7 contains 2 noncollagenous domains (NC1 and NC2) and a central collagenous domain, forming anchoring fibrils (AFs) that are critical to dermal-epidermal basement cohesion (2, 4). Mutations in COL7A1 lead to disruptions in keratinocyte adhesion, reducing mucocu-BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy. METHODS. Autologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm 2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years. RESULTS. No participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019). CONCLUSION. C7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patientreported outcomes. TRIAL REGISTRATION. Clinicaltrials.gov identifier: NCT01263379.

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

“…Gene therapies aim at replacing or correcting disease-causing gene mutations in ex vivo patient cells, including induced pluripotent stem cells (iPSCs) [97], fibroblasts [98,99], and keratinocytes with high growth potential, termed holoclones. Different strategies ranging from retroviral-mediated gene transfer to genome editing (e.g., TALENs and CRISP/CAS9 systems) [100,101,102,103,104,105] can be used for gene correction in patient cells. In the approaches which are already in trials, primary keratinocytes from patients are transduced in vitro with retroviral vectors encoding a normal protein, expanded in the laboratory, and transplanted as gene-corrected epidermal sheets (i.e., autologous cultured epidermal grafts) in patients [102,103,104,105].…”

“…Different strategies ranging from retroviral-mediated gene transfer to genome editing (e.g., TALENs and CRISP/CAS9 systems) [100,101,102,103,104,105] can be used for gene correction in patient cells. In the approaches which are already in trials, primary keratinocytes from patients are transduced in vitro with retroviral vectors encoding a normal protein, expanded in the laboratory, and transplanted as gene-corrected epidermal sheets (i.e., autologous cultured epidermal grafts) in patients [102,103,104,105]. These therapeutic interventions entered clinical trials for RDEB (ClinicalTrials.gov Identifier: NCT01263379 and NCT02984085) [103,104], and JEB (ClinicalTrials.gov Identifier: NCT02984085) with exciting results in the latter [105].…”

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020

“…This approach necessitates multiple injections, which can be painful, to the eroded areas of skin, and how long the corrected resident fibroblasts are present and remain active in situ is unclear. Another company (Abeona Therapeutics, Inc.) cultures autologous keratinocytes from the skin of patients with RDEB, followed by genetic correction ex vivo and development of epidermal sheaths, which can then be grafted to the denuded areas of the patient's skin [29,30]. These studies have utilized a lentiviral vector that allows incorporation of the COL7A1 cDNA into the genome of the recipient cells.…”

Gene therapy in radiation oncology

“…Teoreticky tedy tyto metody umožňují opravu onkogenních mutací v nádorových nebo i nenádorových buňkách. Byly již klinicky využity jednak k výrobě modifikovaných protinádorových lymfocytů, jednak k opravě here-ditárních onemocnění kůže nebo kostní dřeně [7][8][9].…”