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Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial

Di, W-L; Lwin, SM; Petrova, A; Bernadis, C; Syed, F; Farzaneh, F; Moulding, DM; ... Qasim, W; + view all (2019) Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial. Human Gene Therapy , 30 (9) pp. 1067-1078. 10.1089/hum.2019.049. Green open access

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Abstract

Netherton Syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in SPINK5. It is a debilitating condition with notable mortality in the early years of life. There is no curative treatment. We undertook a non-randomized, open-label, feasibility and safety study using autologous keratinocytes transduced with a lentiviral vector encoding SPINK5 under the control of the human involucrin promoter. Six NS subjects were recruited and gene-modified epithelial sheets were successfully generated in three out of five subjects. The sheets exhibited expression of correctly sized LEKTI protein after modification. One subject was grafted with a 20cm2 gene-modified graft on the left anterior thigh without any adverse complications and was monitored by serial sampling for 12 months. Recovery within the graft area were compared against an area outside by morphology, pro-viral copy number and expression of the SPINK5 encoded protein, LEKTI, and its down-stream target kallikrein 5, which exhibited transient functional correction. The study confirmed the feasibility of generating lentiviral gene-modified epidermal sheets for inherited skin diseases such as NS, but sustained LEKTI expression is likely to require the identification, targeting and engraftment of long-lived keratinocyte stem cell populations for durable therapeutic effects. Important learning points for the application of gene modified epidermal sheets are discussed.

Type: Article
Title: Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2019.049
Publisher version: https://doi.org/10.1089/hum.2019.049
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: gene therapy, Netherton syndrome, SPINK5, epidermal sheet culture, lentiviral vector
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 > Developmental Biology and Cancer Dept
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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10078072
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