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

Wei Li Di, Su M. Lwin, Anastasia Petrova, Catina Bernadis, Farhatullah Syed, Farzin Farzaneh, Dale Moulding, Anna E. Martinez, Neil J. Sebire, Dyanne Rampling, Alex Virasami, Mozheh Zamiri, Wei Wang, Havinder Hara, Tendai Kadiyirire, Alya Abdul-Wahab, Magdalena Martinez-Queipo, John I. Harper, John A. McGrath, Adrian J. ThrasherJemima E. Mellerio, Waseem Qasim

研究成果: Article同行評審

28 引文 斯高帕斯(Scopus)

摘要

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 nonrandomized, 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 of five subjects. The sheets exhibited expression of correctly sized lympho-epithelial Kazal-type-related inhibitor (LEKTI) protein after modification. One subject was grafted with a 20 cm2 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 was compared against an area outside by morphology, proviral copy number and expression of the SPINK5 encoded protein, LEKTI, and its downstream 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.

原文English
頁(從 - 到)1067-1078
頁數12
期刊Human Gene Therapy
30
發行號9
DOIs
出版狀態Published - 2019 9月

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 分子生物學
  • 遺傳學

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