Abstract Number: PB0650
Meeting: ISTH 2021 Congress
Background: Hemophilia A (HemA) is a disease caused by absent or deficient FVIII protein. Gene therapy targeting hematopoietic stem cells is an attractive approach to treating this disease. Emerging evidence points to the lung being a reservoir for hematopoietic progenitors/stem cells (HSCs), in addition to bone marrow. Our previous data demonstrated that specific promoter GP1bα (G) can drive external factor VIII (FVIII) gene and achieve long-term expression of FVIII protein in megakaryocytes by transducing HSCs in mice.
Aims: Deliver a lentiviral vector (LV) intranasally into HemA mice to correct FVIII deficiency and improve coagulation.
Methods: HemA mice were conditioned with N-acetylcysteine and dexamethasone to reduce lung mucus and the immune response, respectively. They were then administered a LV with a titer of 1.1×109 ifu/mL intranasally. The LV contained a megakaryocyte-specific Gp1ba-promoter driven FVIII gene to target expression to platelets.
Results: Using flow cytometry, we found that IN delivery of GFP containing LVs (2.5×109 ifu/mL) produced up to 0.075% positive GFP expressing-platelets after 4 days. When a vector containing the FVIII gene (G-F8-LV) was delivered intranasally (2.5×109 ifu/mL), FVIII expression in platelets was detectable by ELISA at a level of 0.4 mU/108 platelets. Additionally, rotational thromboelastometry (ROTEM) assays using whole blood from the gene therapy group showed that the mice had functional improvements at days 7 and 30 post-treatment.
Conclusions: These data demonstrate that we have succeeded in producing FVIII expressing platelets and partially corrected HemA phenotype in mice via intranasal delivery of G-FVIII-LVs in the lung. The benefit of FVIII expression and storage in platelet α-granules is to protect FVIII from naturalizing antibodies and to decrease the possibility of inducing inhibitory antibodies. The IN delivery of LVs encoding FVIII gene targeting lung would be a promising option for therapeutic treatment of hemophilia patients.
To cite this abstract in AMA style:Rementer CW, Li C, Chen C-, Miao CH. A Novel Strategy for Platelet-specific Gene Therapy for the Treatment of Hemophilia A via Intranasal Delivery Lentiviral Vectors Containing Factor VIII [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-novel-strategy-for-platelet-specific-gene-therapy-for-the-treatment-of-hemophilia-a-via-intranasal-delivery-lentiviral-vectors-containing-factor-viii/. Accessed December 7, 2021.
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