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Long-term correction of hemorrhagic diathesis in hemophilia A mice by an AAV-delivered hybrid FⅧcomposed of the human heavy chain and the rat light chain

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Frontiers of Medicine 2022年第4期16卷 584-595页

作者： Jianhua Mao Yun Wang Wei Zhang Yan Shen Guowei Zhang Wenda Xi Qiang Wang Zheng Ruan Jin Wang Xiaodong Xi Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsCollaborative Innovation Center of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Institute of Hematology State Key Laboratory for Medical Genomics and Department of HematologyCollaborative Innovation Center of Systems BiomedicinePôle SinoFrançais des Sciences du Vivant et GenomiqueRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Research Center for Experimental Medicine Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China The School of Medicine Hangzhou Normal UniversityHangzhou 310036China Shanghai Institute of Hypertension Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

Conventional therapies for hemophilia A(HA)are prophylactic or on-demand intravenous FⅧinfusions.However,they are expensive and inconvenient to perform.Thus,better strategies for HA treatment must be developed.In this study,a recombinant FⅧcDNA encoding a human/rat hybrid FⅧwith an enhanced procoagulant potential for adeno-associated virus(AAV)-delivered gene therapy was developed.Plasmids containing human FⅧheavy chain(hHC),human light chain(hLC),and rat light chain(rLC)were transfected into cells and hydrodynamically injected into HA mice.Purified AAV viruses were intravenously injected into HA mice at two doses.Results showed that the hHC+rLC protein had a higher activity than the hHC+hLC protein at comparable expression levels.The specific activity of hHC+rLC was about 4-to 8-fold higher than that of their counterparts.Hydrodynamic injection experiments obtained consistent results.Notably,the HA mice undergoing the AAV-delivered hHC+rLC treatment exhibited a visibly higher activity than those treated with hHC+hLC,and the therapeutic effects lasted for up to 40 weeks.In conclusion,the application of the hybrid FⅧ(hHC+rLC)via an AAV-delivered gene therapy substantially improved the hemorrhagic diathesis of the HA mice.These data might be of help to the development of optimized FⅧexpression cassette for HA gene therapy.

关键词： hemophilia A adeno-associated virus(AAV) human/rat hybrid factorⅧ gene therapy dual chain strategy

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