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Platelet gene therapy by lentiviral gene delivery to hematopoietic stem cells restores hemostasis and induces humoral immune tolerance in FIX(null) mice. Mol Ther 2014 Jan;22(1):169-77

Date

09/18/2013

Pubmed ID

24042561

Pubmed Central ID

PMC3978792

DOI

10.1038/mt.2013.197

Scopus ID

2-s2.0-84891836194 (requires institutional sign-in at Scopus site)   48 Citations

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.

Author List

Chen Y, Schroeder JA, Kuether EL, Zhang G, Shi Q

Author

Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Disease Models, Animal
Factor IX
Gene Expression
Genetic Therapy
Genetic Vectors
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Hemophilia B
Hemostasis
Humans
Immune Tolerance
Immunity, Humoral
Lentivirus
Mice
Mice, Knockout
Phenotype
Proviruses
Transduction, Genetic