title: Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy.
abstract: BACKGROUND
  Ongoing efforts to improve pulmonary gene transfer thereby enabling gene therapy for the treatment of lung diseases, such as cystic fibrosis (CF), has led to the assessment of a lentiviral vector (simian immunodeficiency virus [SIV]) pseudotyped with the Sendai virus envelope proteins F and HN.
  
  
  OBJECTIVE
  To place this vector onto a translational pathway to the clinic by addressing some key milestones that have to be achieved.
  
  
  METHODS
  F/HN-SIV transduction efficiency, duration of expression, and toxicity were assessed in mice. In addition, F/HN-SIV was assessed in differentiated human air-liquid interface cultures, primary human nasal epithelial cells, and human and sheep lung slices.
  
  
  RESULTS
  A single dose produces lung expression for the lifetime of the mouse (~2 yr). Only brief contact time is needed to achieve transduction. Repeated daily administration leads to a dose-related increase in gene expression. Repeated monthly administration to mouse lower airways is feasible without loss of gene expression. There is no evidence of chronic toxicity during a 2-year study period. F/HN-SIV leads to persistent gene expression in human differentiated airway cultures and human lung slices and transduces freshly obtained primary human airway epithelial cells.
  
  
  CONCLUSIONS
  The data support F/HN-pseudotyped SIV as a promising vector for pulmonary gene therapy for several diseases including CF. We are now undertaking the necessary refinements to progress this vector into clinical trials.
authors.affiliation: Department of Gene Therapy, Imperial College at the National Heart and Lung Institute, Manresa Road, London, UK.
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Cuixiang
authors.initials: C
authors.lastname: Meng
authors.forename: Raymond
authors.initials: R
authors.lastname: Farley
authors.forename: Mario
authors.initials: M
authors.lastname: Chan
authors.forename: Nikki K
authors.initials: NK
authors.lastname: Newman
authors.forename: Andrea
authors.initials: A
authors.lastname: Brum
authors.forename: Jun
authors.initials: J
authors.lastname: You
authors.forename: Angela
authors.initials: A
authors.lastname: Kerton
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: A Christopher
authors.initials: AC
authors.lastname: Boyd
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Higgins
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Gill
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Hyde
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Innes
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015302:Simian Immunodeficiency Virus