Human Molecular Genetics, Vol 6, 927-933, Copyright © 1997 by Oxford University Press
RA Freiberg, KA Choate, H Deng, ES Alperin, LJ Shapiro and PA Khavari
Single gene recessive genetic skin disorders offer attractive prototypes
for the development of therapeutic cutaneous gene delivery. We have
utilized X-linked ichthyosis (XLI), characterized by loss of function of
the steroid sulfatase arylsulfatase C (STS), to develop a model of
corrective gene delivery to human skin in vivo. A new retroviral expression
vector was produced and utilized to effect STS gene transfer to primary
keratinocytes from XLI patients. Transduction was associated with
restoration of full-length STS protein expression as well as steroid
sulfatase enzymatic activity in proportion to the number of proviral
integrations in XLI cells. Transduced and uncorrected XLI keratinocytes,
along with normal controls, were then grafted onto immunodeficient mice to
regenerate full thickness human epidermis. Unmodified XLI keratinocytes
regenerated a hyperkeratotic epidermis lacking STS expression with
defective skin barrier function, effectively recapitulating the human
disease in vivo. Transduced XLI keratinocytes from the same patients,
however, regenerated epidermis histologically indistinguishable from that
formed by keratinocytes from patients with normal skin. Transduced XLI
epidermis demonstrated STS expression in vivo by immunostaining as well as
a normalization of histologic appearance at 5 weeks post-grafting. In
addition, transduced XLI epidermis demonstrated a return of barrier
function parameters to normal. These findings demonstrate corrective gene
delivery in human XLI patient skin tissue at both molecular and functional
levels and provide a model of human cutaneous gene therapy.
ARTICLES
A model of corrective gene transfer in X-linked ichthyosis
Dermatology Service, V.A. Palo Alto Health Care System, CA 94304, USA.
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