The impact of GPIbα on platelet‐targeted FVIII gene therapy in hemophilia A mice with pre‐existing anti‐FVIII immunity
Author(s): ,
Juan Chen
Affiliations:
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, USA. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
,
Jocelyn A. Schroeder
Affiliations:
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, USA. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA. Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, USA. MACC Fund Research Center, Milwaukee, USA
,
Xiaofeng Luo
Affiliations:
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, USA
,
Robert R. Montgomery
Affiliations:
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, USA. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA. Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, USA. MACC Fund Research Center, Milwaukee, USA
Qizhen Shi
Affiliations:
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, USA. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA. Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, USA. MACC Fund Research Center, Milwaukee, USA
Correspondence: Qizhen Shi, Section of Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA|Tel.: +1 414 937 3853|E‐mail: qizhen.shi@bcw.edu
ISTH Academy. Shi Q. Mar 1, 2019; 273402
Dr. Qizhen Shi
Dr. Qizhen Shi
Login now to access Regular content available to all registered users.

Access to Premium content is currently a membership benefit.

Click here to join ISTH or renew your membership.

You may also access ISTH content "anytime, anywhere" with the FREE ISTH Academy App for iOS and Android.
Journal Abstract
Discussion Forum (0)
Rate & Comment (0)


Background
We have previously demonstrated that von Willebrand factor (VWF) is essential in platelet‐specific FVIII (2bF8) gene therapy of hemophilia A (HA) with inhibitory antibodies (inhibitors). At the site of injury, platelet adherence is initiated by VWF binding to the platelet GPIb complex.
Objective
To investigate the impact of GPIbα on platelet gene therapy of HA with inhibitors.
Methods
Platelet‐FVIII expression was introduced by 2bF8 lentivirus (2bF8LV) transduction of hematopoietic stem cells (HSCs) from GPIbα (Ib) mice or rhF8‐primed FVIII (F8) mice followed by transplantation into lethally irradiated rhF8‐primed F8 recipients. Animals were analyzed by flow cytometry, FVIII assays and the tail bleeding test.
Results
After transplantation, 99% of platelets were derived from donors. The macrothrombocytopenia phenotype was maintained in F8 mice that received 2bF8LV‐transduced Ib HSCs (2bF8‐Ib/F8). The platelet‐FVIII expression level in 2bF8‐Ib/F8 recipients was similar to that obtained from F8 mice that received 2bF8LV‐transduced F8 HSCs (2bF8‐F8/F8). The tail bleeding test showed that the remaining hemoglobin level in the 2bF8‐Ib/F8 group was significantly higher than in the F8 control group, but there was no significant difference between the 2bF8‐Ib/F8 and 2bF8‐F8/F8 groups. The half‐life of inhibitor disappearance time was comparable between the 2bF8‐Ib/F8 and 2bF8‐F8/F8 groups. The rhF8 re‐challenge did not elicit a memory immune response once inhibitor titers dropped to undetectable levels after 2bF8 gene therapy.
Conclusion
GPIbα does not significantly impact platelet gene therapy of HA with inhibitors. 2bF8 gene therapy restores hemostasis and promotes immune tolerance in HA mice with pre‐existing immunity.
Keyword(s)
FVIII , gene therapy, GPIbα, hemophilia A, platelet
Code of conduct/disclaimer available in General Terms & Conditions

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies