title: Ex vivo transduction and transplantation of bone marrow cells for liver gene delivery of alpha1-antitrypsin.
abstract: Adult stem cell-based gene therapy holds several unique advantages including avoidance of germline or other undesirable cell transductions. We have previously shown that liver progenitor (oval) cells can be used as a platform for liver gene delivery of human alpha1-antitrypsin (hAAT). However, this cell source cannot be used in humans for autologous transplantation. In the present study, we tested the feasibility of bone marrow (BM) cell-based liver gene delivery of hAAT. In vitro studies showed that BM cells can be transduced by lentiviral vector (Lenti-CB-hAAT) and recombinant adeno-associated viral vectors (rAAV1-CB-hAAT, and rAAV8-CB-hAAT). Transplantation studies showed that transplanted BM cells homed into liver, differentiated into hepatocytes and expressed hAAT in the liver. Importantly, we showed that transplantation of rAAV8-CB-hAAT vector-transduced BM cells resulted in sustained levels of hAAT in the systemic circulation of recipient mice. These results demonstrated that rAAV vector-mediated BM cell-based liver gene therapy is feasible for the treatment of AAT deficiency and implies a novel therapy for the treatment of liver diseases.
authors.affiliation: Department of Pharmaceutics, University of Florida, Gainesville, FL, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Lu
authors.forename: Rafal P
authors.initials: RP
authors.lastname: Witek
authors.forename: Lung-Ji
authors.initials: LJ
authors.lastname: Chang
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Marda
authors.initials: M
authors.lastname: Jorgensen
authors.forename: Bryon
authors.initials: B
authors.lastname: Petersen
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000418:Albumins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic / Q000379:methods; D014998:Y Chromosome / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D000418:Albumins; D000515:alpha 1-Antitrypsin; D049452:Green Fluorescent Proteins