HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Ex-vivo gene therapy restores LEKTI activity and corrects the architecture of Netherton syndrome-derived skin grafts.

Abstract
Netherton syndrome (NS) is a debilitating congenital skin disorder caused by mutations in the SPINK5 gene encoding the lymphoepithelial Kazal-type-related inhibitor (LEKTI). It is characterized by defective keratinization, recurrent infections, and hypernatraemic dehydration with a mortality rate of about 10% in the first year of life. Currently, there are no curative treatments for NS. We have developed a HIV-1 based, self-inactivating lentiviral vector to express SPINK5 in keratinocytes as part of an ex-vivo gene therapy strategy for NS. High transduction efficiency was achieved in NS keratinocytes and reconstitution of LEKTI expression was confirmed in previously deficient cells. These genetically corrected keratinocytes were further tested in an in vitro organotypic culture (OTC) system and in vivo mouse/human skin engraftment model. Results showed correction of epidermal architecture in both OTCs and regenerated skin grafts. Importantly, the results from corrected skin grafts indicated that even where detectable LEKTI expression was restored to a limited numbers of cells, a wider bystander benefit occurred around these small populations. As LEKTI is a secreted protein, the genetically modified graft may provide not only an immediate local protective barrier, but also act as a source of secreted LEKTI providing a generalized benefit following ex-vivo gene therapy.
AuthorsWei-Li Di, Fernado Larcher, Ekaterina Semenova, Gill E Talbot, John I Harper, Marcela Del Rio, Adrian J Thrasher, Waseem Qasim
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 2 Pg. 408-16 (Feb 2011) ISSN: 1525-0024 [Electronic] United States
PMID20877344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Proteinase Inhibitory Proteins, Secretory
  • SPINK5 protein, human
  • Serine Peptidase Inhibitor Kazal-Type 5
Topics
  • Animals
  • Cell Line
  • Cell Proliferation
  • Cells, Cultured
  • Flow Cytometry
  • Genetic Therapy (methods)
  • Genetic Vectors (genetics)
  • Humans
  • Immunoblotting
  • Keratinocytes (cytology)
  • Lentivirus (genetics)
  • Mice
  • Mice, Nude
  • Microscopy, Fluorescence
  • Netherton Syndrome (therapy)
  • Polymerase Chain Reaction
  • Proteinase Inhibitory Proteins, Secretory (genetics, metabolism)
  • Serine Peptidase Inhibitor Kazal-Type 5

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: