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All Investigators
Qizhen Shi, MD, PhD

Qizhen Shi, MD, PhD

Senior Investigator

Professor of Pediatric Hematology
Department of Pediatrics
Medical College of Wisconsin

Education and Training

Post Doctoral Training
Medical College of Wisconsin

Doctoral Training
Fujian Medical University, Fuzhou, China

Contact Us

Qizhen Shi, MD, PhD

Senior Investigator
Email 414-937-3853 Fax: 414-937-6811

  • Research Interests

    Primary Research Area: Stem Cell Biology/Hematopoiesis

    The research focus in our laboratory is to formulate innovative gene and cell therapeutic approaches for the treatment of hemophiliacs. There are three major areas that we are working on.

    Gene therapy of hemophilia A

    Hemophilia A is a recessive X-linked bleeding disorder resulting from a FVIII deficiency. Although protein replacement therapy is effective for hemophilia A treatment, up to 35% of patients may develop inhibitory antibodies (referred to as inhibitors) that neutralize FVIII activity. Introducing FVIII expression via genetic therapy is an attractive alternative treatment for hemophilia A patients. However, the potential to develop inhibitors to the transgene protein remains a significant concern. We have recently developed a novel gene therapy approach in which FVIII is targeted and stored in platelet α-granules. Using a transgenic mouse model, we showed that FVIII can be specifically expressed and stored together with its carrier protein, VWF, in platelet α-granules when it is driven by the platelet-specific αIIb promoter (2bF8) and that platelet-FVIII can correct the murine hemophilia A phenotype even in the presence of high-titer inhibitors. To apply this gene therapy to a clinically translatable protocol, we use lentiviral gene delivery to hematopoietic stem cells (HSCs) to introduce FVIII expression in platelets. We found that 2bF8 lentiviral gene delivery to HSCs can not only restore hemostasis, but also induce antigen-specific immune tolerance in hemophilia A mice. Our current work aims to 1) further optimize this approach; 2) dissect the potential underlying mechanisms by which immune tolerance is induced after platelet gene therapy; and 3) translate findings made in laboratory animals to human patients. 

    Gene therapy of hemophilia B 

    Hemophilia B is a genetic bleeding disorder which results from a FIX deficiency. Although the incidence of anti-FIX inhibitor development is lower (5%) in hemophilia B patients after protein replacement therapy, anaphylaxis is a daunting problem in inhibitor patients, which limits the use of FIX infusion and increases the risk of morbidity and mortality. Our studies show that FIX can be ectopically expressed and stored in platelet α-granules when it is driven under the same αIIb promoter that we use for platelet-FVIII expression. Platelet-derived FIX, which is fully γ-carboxylated, can rescue bleeding diathesis in hemophilia B mice, but the clinical efficacy is limited in the presence of anti-FIX inhibitors. Although platelet-FIX does not maintain clinical efficacy in the face of inhibitors, targeting FIX expression to platelets is still an attractive potential strategy for gene therapy of hemophilia B. Indeed, our studies demonstrate that 2bF9 gene delivery to HSCs not only restores hemostasis, but also induce FIX-specific immune tolerance in hemophilia B mice. Our current work aims to optimize the FIX expression and develop a protocol for gene therapy of hemophilia B with pre-existing immunity. 

    VWF/FVIII association and FVIII immunity

    While the important association between VWF and FVIII has been investigated for decades, how VWF impacts FVIII immunity is still uncertain. Our studies demonstrate that VWF is essential for maintaining platelet-FVIII efficacy in hemophilia A with inhibitors. VWF reduces inhibitor inactivation of FVIII, exerting a protective effect both in vitro and in vivo. VWF/FVIII association plus the apparent ability of VWF to delay the time-dependent inactivation of FVIII by inhibitors provides mechanisms by which platelet-derived FVIII maintains function even in the presence of inhibitors when FVIII is targeted to platelets for gene therapy of hemophilia A with inhibitors. Our current work aims to investigate the roles of VWF in FVIII immunity in hemophilia A. 

  • Grant Support


    • R01 HL102035, “Platelet-derived FVIII gene therapy of hemophilia A,” 2010 – 2024
    • MACC FUND, “Platelet gene therapy for hemophilia”
    • National Hemophilia Foundation Bridge Award, "Investigation of VWF as an immunomodulator of the immunogenic response towards FVIII," 2018 - 2019.
    • CRI Pilot Research Grant, "Utilizing platelet-targeted gene therapy to induce immune tolerance in experimental autoimmune encephalomyelitis (EAE)," 01/2019 - 12/2019
  • Lab

    Jocelyn Schroeder
    Research Technologist III

    Weiqing Jing, PhD
    Research Scientist II

    Hongyin Yu
    Graduate Student

    Yuanhua Cai
    Predoctoral Fellow

    Jessica Coonen
    Animal Technician

  • Publications

    Selected Publications

    Dr. Qizhen Shi, M.D., Ph.D. has many published papers including:

    • Jing W, Chen J. Cai Y, Chen Y, Schroeder JA, Cui W, Johnson BD, and Shi Q.*  Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice. Blood Adv. 2019 Oct 22;3 (20): 3099–3110. doi:.10.1182/bloodadvances.2019000650. *Corresponding author.
    • Gao C, Schroeder JA, Xue F, Jing W, Cai Y, Subramaniam S, Rao S, Weiler H, Czechowicz A, and Shi Q.* Immunotoxin-mediated non-genotoxic preconditioning for platelet gene therapy of hemophilia A mice. Blood Adv. 2019 Sep 24;3(18):2700-2711. doi: 10.1182/bloodadvances.2019000516. *Corresponding author. Featured article. Article was highlighted in “Advance Notice” Newsletter by Editor-In-Chief. PMCID:PMC6759737.
    • Wang D, Zhang G, Gu J, Shao X, Dai Y, Li J, Pan X, Yao S, Jin Y, Huang J, Shi Q, Chen Z, and Chen S. Platelet-targeted gene therapy of murine hemophilia A using HSPCs derived from genome edited iPSCs. Haematologica. 2019 Jul 11. pii: haematol. 2019.219089. doi: 10.3324/haematol. 2019.219089. [Epub ahead of print] PMID: 31296582. 
    • Chen J, Schroeder JA, Luo X, Montgomery RR, and Shi Q. The impact of GPIbα on platelet-targeted FVIII gene therapy in hemophilia A with pre-existing anti-FVIII immunity. J Thromb Haemost. 2019 Mar;17(3):449-459. doi: 10.1111/jth.14379. PMID: 30609275. PMCID: PMC6397061.
    • Luo X, Chen J, Schroeder JA, Baumgartner KC, Subramaniam M, Hu J, Williams CB, and Shi Q. Platelet gene therapy provokes targeted peripheral tolerance by clonal deletion and induction of antigen-specific regulatory T cells. Front. Immunol 2018 Sep 6; 9: 1950. Doi:10.3389/fimmu.2018.01950. PMID: 30237796. PMCID: PMC6136275.
    • Shi Q. Platelet-targeted gene therapy for hemophilia. Molecular Therapy - Methods & Clinical Development 2018, 9(6): 100-108. Invited review article.
    • Chen Y, Luo X, Chen J, Schroeder JA, Baumgartner KC, Hu J, and Shi Q.* Immune tolerance developed in platelet-targeted FVIII gene therapy is CD4 T cell-mediated. J Thromb Haemost. 2017 Oct;15(10):1994-2004. *Corresponding author. PMID: 28799202. PMCID: PMC5630523. 
    • Chen J, Schroeder JA, Luo X, and Shi Q.* The impact of von Willebrand factor on factor VIII memory immune responses.  Blood Adv. 2017; Aug 22; 1(19):1565-1574. Featured article. Article was highlighted in “Advance Notice” Newsletter by Editor-In-Chief. *Corresponding author. PMID: 28920105. PMCID PMC5600162.
    • Baumgartner KC, Mattson JG, Weiler H, Shi Q,* and Montgomery RR. Targeting FVIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. J Thromb Haemost. 2017 Jan;15(1):98-109. doi: 10.1111/jth.13436. .PMCID: PMC5280575. *Corresponding author. Featured article: “In This Issue”. Tuddenham E. G. D. Platelets are a safe way to deliver factor VIII. After 13 years of preclinical research it is now time for a clinical trial.
    • Haribhai, D., Luo, X., Chen, J., Jia, S., Shi, L., Schroeder, J.A., Hessner, M.J., Aster, D., Hu, J., Williams, C. B., and Shi, Q. TGFβ1 along with other platelet contents augments Treg cells to suppress anti-FVIII immune responses in hemophilia A mice. Blood Advances 2016 Dec 13, 1(2): 139-151. Article was highlighted in “Advance Notice” Newsletter by Editor-In-Chief.
    • Chen, Y., Schroeder, J.A., Chen, J., Luo, X., Baumgartner, K.C., Montgomery R.R., Hu, J., and Shi, Q. The immunogenicity of platelets containing FVIII in murine hemophilia A with or without pre-existing anti-FVIII immunity. Blood2016 Mar 10, 127(10): 1346-54. Featured article: “In This Issue”. Ragni, M.V. Platelet VIII pack evades immune detection. Blood 2016, 127(10): 1222-24. Article also got highlighted as being among the “hottest” new studies by Editor-in-Chief.
    • Baumgartner, K.C, Kuether, E.L., Zhang, G., Weiler, H., Shi, Q.,* and Montgomery, R.R. Native whole blood thrombin generation assay evaluates therapeutic efficacy of plasma and platelet-derived FVIII. J Thromb Haemost. 2015 Dec; 13(12):2210-2219. * Corresponding author.
    • Shi, Q.,* Schroeder, J.A., Kuether E.L., and Montgomery, R.R.  The important role of von Willebrand factor in platelet-derived factor VIII gene therapy of murine hemophilia A in the presence of inhibitory antibodies.  J Thromb Haemost. 2015 July; 13(7): 1301-1309. *Corresponding author.
    • Kanaji, S., Fahs, S.A., Ware, J., Montgomery, R.R., and Shi, Q.  Non-myeloablative conditioning with busulfan prior to hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard Soulier Syndrome. J Thromb Haemost. 2014 Oct; 12(10):1726-32.
    • Mannucci, P.M., Shi, Q., Bonanad, S., and Klamroth, R. Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development.  Haemophilia 2014 Sep; 20 Suppl 6:2-16.
    • Schroeder, J.A., Chen, Y., Fang, J., Wilcox, D.A., and Shi, Q.*  In vivo enrichment of manipulated platelets corrects the murine hemophilic phenotype and induces immune tolerance even using a low multiplicity of infectious. J Thromb Haemost. 2014 Aug; 12(8):1283-93.  *Corresponding author.
    • Fahs, S.A., Hille, M.T., Shi, Q., Weiler, H., and Montgomery, R.R.  Conditional knockout mouse model reveals endothelial cells as the predominant and possibly exclusive source of plasma factor VIII.  Blood 2014 Jun 12; 123(24):3706-13.  Featured article: "In this Issue".  Ed Tuddenham.  In search of the source of factor VIII.  Blood, 2014; 123(24):3691.  Article also got highlighted as being among the "Hottest" new studies by the editors.
    • Shi, Q.,* Kuether, E.L., Chen, Y., Schroeder, J.A., Fahs, S.A., and Montgomery, R.R.  Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells.  Blood 2014; 123(3):395-403. (*Corresponding author)
    • Chen, Y., Schroeder, J.A., Kuether, E.L., Zhang, G., and Shi, Q.*  Lentivirus-mediated platelet gene therapy corrects bleeding diathesis and induces humoral immune tolerance in hemophilia B mice.  Mol Ther. 2014; 22(1):169-77.  *Corresponding author.
    • Du, L.M., Nurden, P., Nurden, A.T., Nichols, T.C., Bellinger, D.A., Jensen, E.S., Haberichter S.L., Merricks, E., Paymer, R.A., Fang, J., Koukouritaki, S.B., Jacobi, P.M., Hawkins, T.B., Cornetta, K., Shi, Q., and Wilcox, D.A.  Platelet alpha-granules containing human factor VIII induce hemostasis for canine hemophilia A. Nat Commun. 2013 Nov 19; 4:2773.
    • Shi, Q.*, Kuether, E.L., Schroeder, J.A., Perry, C.L., Fahs, S.A., Gil, J. C., Montgomery, R.R. FVIII inhibitors: VWF makes a difference in vitro and in vivo. Submitted 2012 (* Corresponding author). J Thromb Haemost. 2012;10(11): 2328–37. (* Corresponding author). [Article published In Focus and accomplished by invited editorial commentary. Ragni, M.V. VWF: Factor VIII Protector and Friend. J Thromb Haemost. 2012;2012;10(11): 2324–2327.
    • Kuether, E.L., Fahs, S.A., Cooley, B.C., Schroeder, J.A., Chen, Y., Montgomery, R.R., Wilcox, D.A.,Shi, Q.  Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-FVIII immunity. J Thromb Haemost. 2012 Aug;10(8):1570-80. [Article published In Focus and accompanied by invited editorial commentary. Chuah, M. and Vanderdriessche, T. Platelet-directed gene therapy overcomes inhibitory antibodies to FVIII. J Thromb Haemost 2012; 10(8): 1566-1569.
    • Kanaji, S., Fahs, S.A., Shi, Q., Haberichter, S.L., and Montgomery, R.R. Contribution of platelet versus endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost. 2012;10(8):1646-52.
    • Montgomery, R.R., Shi, Q. Platelet and endothelial expression of clotting factors for the treatment of hemophilia. Thromb Res. 2012 May; 129 Suppl 2:S46-8.
    • Shi, Q.*, Kuether, E.L., Schroeder, J.A., Fahs, S.A., Montgomery, R. R. Intravascular recovery of VWF and FVIII following intraperitoneal injection and differences from intravenous and subcutaneous injection in mice. Haemophilia. 2012;18(4), 639–46. (* Corresponding author).
    • Kanaji, S., Kuether, E.L., Schroeder, J.A., Fahs, S.A., Ware J., Montgomery, R.R., Shi, Q. Lentivirus-mediated gene therapy of Bernard-Soulier Syndrome in a GPIba deficient mouse model. Mol Ther 2012 Mar;20(3):625-32.
    • Montgomery, R. R. and Shi, Q.   Alternative Strategies for Gene Therapy of Hemophilia. Hematology Am Soc Hematol Educ Program. 2010; 2010: 197-202.
    • Shi, Q.*, Montgomery, R.R. Platelets as delivery systems for disease treatments. Advanced Drug Delivery Reviews. Adv Drug Deliv Rev. 2010;62(12):1196-203 (* Corresponding author).
    • Shi, Q.*, Fahs, S. A., Kuether, E. L., Cooley, B.C., Weiler, H., Montgomery, R. R. Targeting FVIII expression to endothelial cells regenerates a releasable pool of FVIII and restores hemostasis in a mouse model of hemophilia A. Blood 2010, 116(16):3049-57 (* Corresponding author). [Article was highlighted by Vascular Biology Publications Alert 2010]
    • Zhang, G., Shi, Q., Fahs, S. A., Kuether, E.L., Walsh, C. E., Montgomery, R. R. Factor IX ectopically expressed in platelets can be stored in α-granules and corrects the phenotype of hemophilia B mice. Blood 2010, 116(8):1235-43.
    • Shi, Q.*, Fahs, S. A., Wilcox, D. A., Kuether, E.L., Morateck, P.A., Mareno, N., Weiler, H., Montgomery, R. R. Syngeneic transplantation of hematopoietic stem cells (HSC) that are genetically modified to express factor VIII (FVIII) in platelets restores hemostasis to hemophilia A mice with pre-existing FVIII immunity. Blood 2008,112 (7):2713-2721 (* Corresponding author). [Article accompanied by invited editorial commentary. Tuddenham E. G. D. Killing 2 birds with 1 stone. Blood 2008,112 (7):2595]
    • Shi, Q.*, Wilcox, D. A., Fahs, S. A., Fang, J., Johnson B. D., Du, L., Desai, D., and Montgomery, R. R. Lentivirus-mediated platelet-derived factor VIII (FVIII) gene therapy of murine hemophilia A. J Thromb Haemost 2007, 5 (2):352-361 (* Corresponding author).
    • Shi, Q., Wilcox, D.A., Fahs, S.A., Weiler, H., Well, C.C., Cooley, B.C., Desai, D., Morateck, P.A., Gorski, J., and Montgomery, R.R. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Invest 2006, 116 (7):1974-1982. [Article accompanied by invited editorial commentary. High, K.A. The leak stops here: platelets as delivery vehicles for coagulation factors. J Clin Invest 2006, 116 (7): 1840-1842.]
    • Haberichter, S.L., Shi, Q., and Montgomery, R.R. The Regulated Release of VWF and FVIII and the Biologic Implications. Pediatr Blood Cancer. 2006; 46 (5):547-53.
    • Haberichter, S.L., Shi, Q., and Montgomery, R.R. The biology of von Willebrand factor and factor VIII-regulated release. Hematologica Reports 2005, 1 (6): 9-14.
    • Shi, Q.*, Wilcox, D.A., Morateck, P.A., Fahs, S.A., Kenny, D., and Montgomery, R.R. Targeting GPIb(alpha) transgene expression to human megakaryocytes and forming a complete GPIb/IX complex with endogenous GPIb(Beta) and GPIX. J Thromb Haemost. 2004, 2 (11):1989-1997 (* Corresponding author).
    • Wilcox, D.A., Shi, Q., Nurden, P., Haberichter, S.L., Rosenberg, J.B., Jonhnson, B.D., nurden, A.T., White, II G.C., and Montgomery, R.R. Induction of megakaryocytes to synthesize and store a releasable pool of human FVIII. J Thromb Haemost. 2003, 1:2477-2489.
    • Yarovoi, H., Kufrin, D., Eslin, D.E., Thornton, M.A., Haberichter, S.L., Shi, Q., Zhu, H., Camire, R., Frkharzadeh, S.S. Kowalska, M.A., Wilcox, D.A., Montgomery, R.R., and Poncz, M. Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment. Blood 2003, 102 (12):4006-4013.
    • Shi, Q., Wilcox, D.A., Fahs, S.A., Kroner, P.A., and Montgomery, R.R. Expression of human factor VIII under control of the IIb promoter in megakaryocytic cell line as well as storage together with VWF. Mol. Genet. and Metab. 2003, 79 (1): 25-33.

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