title: Permanent partial phenotypic correction and tolerance in a mouse model of hemophilia B by stem cell gene delivery of human factor IX.
abstract: Immune responses against an introduced transgenic protein are a potential risk in many gene replacement strategies to treat genetic disease. We have developed a gene delivery approach for hemophilia B based on lentiviral expression of human factor IX in purified hematopoietic stem cells. In both normal C57Bl/6J and hemophilic 129/Sv recipient mice, we observed the production of therapeutic levels of human factor IX, persisting for at least a year with tolerance to human factor IX antigen. Secondary and tertiary recipients also demonstrate long-term production of therapeutic levels of human factor IX and tolerance, even at very low levels of donor chimerism. Furthermore, in hemophilic mice, partial functional correction of treated mice and phenotypic rescue is achieved. These data show the potential of a stem cell approach to gene delivery to tolerize recipients to a secreted foreign transgenic protein and, with appropriate modification, may be of use in developing treatments for other genetic disorders.
authors.affiliation: Gene Therapy Research Group, Faculty of Medicine, Imperial College London, South Kensington, UK. brian.bigger@ndcls.ox.ac.uk
authors.forename: B W
authors.initials: BW
authors.lastname: Bigger
authors.forename: E K
authors.initials: EK
authors.lastname: Siapati
authors.forename: A
authors.initials: A
authors.lastname: Mistry
authors.forename: S N
authors.initials: SN
authors.lastname: Waddington
authors.forename: M S
authors.initials: MS
authors.lastname: Nivsarkar
authors.forename: L
authors.initials: L
authors.lastname: Jacobs
authors.forename: R
authors.initials: R
authors.lastname: Perrett
authors.forename: M V
authors.initials: MV
authors.lastname: Holder
authors.forename: C
authors.initials: C
authors.lastname: Ridler
authors.forename: G
authors.initials: G
authors.lastname: Kemball-Cook
authors.forename: R R
authors.initials: RR
authors.lastname: Ali
authors.forename: S J
authors.initials: SJ
authors.lastname: Forbes
authors.forename: C
authors.initials: C
authors.lastname: Coutelle
authors.forename: N
authors.initials: N
authors.lastname: Wright
authors.forename: M
authors.initials: M
authors.lastname: Alison
authors.forename: A J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: D
authors.initials: D
authors.lastname: Bonnet
authors.forename: M
authors.initials: M
authors.lastname: Themis
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D002478:Cells, Cultured; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D002836:Hemophilia B / Q000097:blood / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes
chemical_list: D000941:Antigens; D049452:Green Fluorescent Proteins; D005164:Factor IX