TY - JOUR
T1 - Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome
T2 - Lessons Learned from a Phase 1 Trial
AU - Di, Wei Li
AU - Lwin, Su M.
AU - Petrova, Anastasia
AU - Bernadis, Catina
AU - Syed, Farhatullah
AU - Farzaneh, Farzin
AU - Moulding, Dale
AU - Martinez, Anna E.
AU - Sebire, Neil J.
AU - Rampling, Dyanne
AU - Virasami, Alex
AU - Zamiri, Mozheh
AU - Wang, Wei
AU - Hara, Havinder
AU - Kadiyirire, Tendai
AU - Abdul-Wahab, Alya
AU - Martinez-Queipo, Magdalena
AU - Harper, John I.
AU - McGrath, John A.
AU - Thrasher, Adrian J.
AU - Mellerio, Jemima E.
AU - Qasim, Waseem
N1 - Publisher Copyright:
© 2019 by Mary Ann Liebert, Inc., publishers.
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
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U2 - 10.1089/hum.2019.049
DO - 10.1089/hum.2019.049
M3 - Article
C2 - 31288584
AN - SCOPUS:85072746303
SN - 1043-0342
VL - 30
SP - 1067
EP - 1078
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 9
ER -