title: Long-term type VII collagen restoration to human epidermolysis bullosa skin tissue.
abstract: In spite of advances in the molecular diagnosis of recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disease due to a deficiency of type VII collagen at the basement membrane zone (BMZ) of stratified epithelium, current therapy is limited to supportive palliation. Gene delivery has shown promise in short-term experiments; however, its long-term sustainability through multiple turnover cycles in human tissue has awaited confirmation. To characterize approaches for long-term genetic correction, retroviral vectors were constructed containing long terminal repeat-driven full-length and epitope-tagged COL7A1 cDNA and evaluated for durability of type VII collagen expression and function in RDEB skin tissue regenerated on immune-deficient mice. Type VII collagen expression was maintained for 1 year in vivo, or over 12 epidermal turnover cycles, with no abnormalities in skin morphology or self-renewal. Type VII collagen restoration led to correction of RDEB disease features, including reestablishment of anchoring fibrils at the BMZ. This approach confirms durably corrective and noninjurious gene delivery to long-lived epidermal progenitors and provides the foundation for a human clinical trial of ex vivo gene delivery in RDEB.
authors.affiliation: Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94304, USA.
authors.forename: Zurab
authors.initials: Z
authors.lastname: Siprashvili
authors.forename: Ngon T
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Bezchinsky
authors.forename: M Peter
authors.initials: MP
authors.lastname: Marinkovich
authors.forename: Alfred T
authors.initials: AT
authors.lastname: Lane
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000818:Animals; D002472:Cell Transformation, Viral; D003094:Collagen; D018076:DNA, Complementary; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008979:Moloney murine leukemia virus / Q000235:genetics; D012867:Skin / Q000378:metabolism; D016038:Skin Transplantation; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D018076:DNA, Complementary; D003094:Collagen