Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa

Abstract

BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS. In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 10 6 cells/cm 2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS. Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION. To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for insight.jci.org

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.…”

EBGene trial: patient preselection outcomes for the European GENEGRAFT ex vivo phase I/II gene therapy trial for recessive dystrophic epidermolysis bullosa

“…Lwin et al . reported a similar observation in one patient who had been treated with intradermal injections of gene‐modified autologous fibroblasts in a phase I trial and had positive enzyme‐linked immunosorbent assay (ELISA) and enzyme‐linked immunosorbent spot (ELISpot) but negative indirect immunofluorescence (IIF) and no autoimmune symptoms after treatment …”

Basement membrane collagens and disease mechanisms

“…While, stem cell treatment employing iPSCs for some tissues/diseases may have its challenges, enormous progress has been made, making this an exciting approach [154]. For RDEB clinical trials employing ex vivo retroviral transduction of patient keratinocytes or fibroblasts to induce collagen VII expression followed by grafting or fibroblast injection, respectively, has shown promise [145,155]. These represent mutation-independent approaches for BM collagens.…”

“…Mitochondrial dysfunction and dysregulation of autophagy resulting from collagen VI or XV/XVIII deficiency was ameliorated by dietary and pharmacological treatments when tested in mice and patient-derived cells [82,37,123,126], indicating a convergent mechanism and treatment. Re-instating collagen expression via cell graft or cell transplant represents a different approach and has shown promise for collagen VI and VII [81,145,155,129]. Re-instating Col6a1 expression also rescued the defective muscle stem cell renewal in Col6a1 −/− mice, which was recalcitrant to autophagy treatment [81], suggesting a combinatorial therapy may be required.…”