title: Platelet gene therapy by lentiviral gene delivery to hematopoietic stem cells restores hemostasis and induces humoral immune tolerance in FIX(null) mice.
abstract: Here, we developed a clinically translatable platelet gene therapy approach for hemophilia B. Platelet-targeted FIX (2bF9) expression was introduced by transplantation of hematopoietic stem cells (HSCs) transduced with 2bF9 lentivirus (LV). Sustained therapeutic levels of platelet-FIX expression were obtained in FIX(null) mice that received 2bF9 LV-transduced HSCs. Approximately 6-39% of the platelets expressed FIX in the transduced recipients, which was sufficient to rescue the bleeding diathesis in FIX(null) mice in tail clipping models. Sequential bone marrow transplantation demonstrated that platelet-FIX expression in the secondary recipients was sustained, leading to phenotypic correction. Notably, none of the transduced recipients developed anti-FIX antibodies after platelet gene therapy. Only one of the nine recipients developed a low titer of inhibitory antibodies (1.6 BU/ml) after challenge with rhFIX. These data suggest that platelet gene therapy can not only restore hemostasis but also induce immune tolerance in hemophilia B mice, indicating that this approach may be a promising strategy for gene therapy of hemophilia B in humans.
authors.affiliation: 1] Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA [2] Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA [2] Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA [3] Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Jocelyn A
authors.initials: JA
authors.lastname: Schroeder
authors.affiliation: 1] Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA [2] Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA [3] Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Kuether
authors.affiliation: School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Zhang
authors.affiliation: 1] Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA [2] Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA [3] Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA [4] MACC Fund Research Center, Milwaukee, Wisconsin, USA.
authors.forename: Qizhen
authors.initials: Q
authors.lastname: Shi
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004195:Disease Models, Animal; D005164:Factor IX / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D002836:Hemophilia B / Q000235:genetics / Q000276:immunology / Q000628:therapy; D006487:Hemostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D056724:Immunity, Humoral / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011533:Proviruses / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D005164:Factor IX
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