BACKGROUND: Netherton syndrome (NS, MIM 256500) is a potential live threatening 
autosomal-recessive skin disorder clinically characterized by the trias of 
congenital erythroderma, hair shaft anomalies and atopic diathesis. It is caused 
by mutations in the gene SPINK5 resulting in a deficiency of its processed 
protein named lympho-epithelial Kazal-type related inhibitor (LEKTI). LEKTI 
controls the activity of several serine proteases in the skin that are involved 
in terminal differentiation. Loss of LEKTI results in protease hyperactivity, 
increased degradation of intercellular junctions, reduced stratum corneum 
adhesion and impaired skin barrier function. Today NS can only be treated 
symptomatically.
OBJECTIVE: Does gene transfer offer a therapeutic option for NS in the future?
METHODS: A recombinant adeno-associated virus type 2 vector was constructed 
containing the full length cDNA (rAAV2/C-SPINK5) of functional human LEKTI. 
Infectious virus particles were used for transfection of 
LEKTI-deficient-keratinocytes of NS patients in vitro.
RESULTS: Gene transfer of SPINK5 in NS-keratinocytes led to a five-fold increase 
in mRNA expression of SPINK5 reaching almost 75% of normal value. The 
functionality of the expressed LEKTI was proven in a hydrolytic activity assay 
demonstrating that the activity of LEKTI after gene transfer increased closely 
to the level seen in keratinocytes of healthy individuals.
CONCLUSION: The results provide first evidence that gene transfer of SPINK5 
results in increased LEKTI activity in NS-keratinocytes, thus offering a 
rational to further pursue such a gene therapy approach for NS.