Thrasher, A;
(2019)
Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.
JCI Insight
, 4
(11)
, Article e126243. 10.1172/jci.insight.126243.
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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 selfinactivating 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 received 3 intradermal injections (~1 million cells/cm2 of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. 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 to non-injected skin in 3 of 4 subjects with 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 one 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 one-year post-gene therapy. These data provide a rationale for phase II studies for further clinical evaluation.
| Type: | Article |
|---|---|
| Title: | Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/jci.insight.126243 |
| Publisher version: | https://doi.org/ 10.1172/jci.insight.126243 |
| Language: | English |
| Additional information: | This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10072941 |
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