Project Title. Blocking the immune response to Helper-dependent adenovirus vector for improved Hemophilia A gene therapy. Project Abstract. Hemophilia A (HA) is a common disorder of coagulation caused by deficiency of factor VIII (FVIII). The mainstay of treatment has been replacement therapy with recombinant human FVIII. However, because of high cost, access to therapy, and inhibitory antibody formation, patients continue to suffer from significant long-term morbidity and mortality. Our development of an optimized helper-dependent adenoviral gene vector (HDAds) system has enabled us to achieve long term expression of both secreted and intracellular transgenes without chronic toxicity and persistence of vector using both small and large animal models. However, acute toxicity remains an obstacle to clinical translation. To overcome this, we propose to develop immune suppressive HDAds expressing SOCS1 and/or coding TLR9 inhibitor sequences. However, because of the great redundancy of the innate immune system, we propose to develop adjunctive therapy in the form of hemofiltration that has already to be clinically-beneficial to remove the acute immune components in the context of sepsis. We will combine hemofiltration with improved immunosuppressive HDAds in safety studies in nonhuman primates. Ultimately, we will apply this approach to the preclinical treatment of FVIII deficiency in murine and canine HA . To address the potential adaptive immune response to FVIII therapy, we will co-express von Willebrand Factor (vWF) with FVIII. With these studies, we will address three important questions in genetic therapy for hemophilia A i) Can we decrease the innate immune response to HDAds? ii) Can we improve the efficacy of FVIII expression in HA model? iii) Can we decrease the innate immune response in nonhuman primate model with adjunctive hemofiltration? The overall goal of this application is to establish the safe and effective HA gene therapy with helper-dependent adenoviral vectors (HDAds) combined with hemofiltration that can be readily translated in the clinical arena for future clinical trials. During this mentored phase (K99), I will improve the therapeutic index of HDAd for HA therapy by combining cell autonomous immune suppression of the innate immune response, physical clearance of non-cell autonomous humoral factors, and stabilization factor of FVIII,. The mentored phase (K99) will occur at Baylor College of Medicine under the guidance of Dr. Brendan Lee. In the subsequent independent investigator phase (R00), I will apply this hybrid HDAds to canine HA in preparation for clinical studies. I will also evaluate the therapeutic effect of hemofiltration-assisted hybrid HDAds injection in nonhuman primates.
. Hemophilia A (HA) is a common disorder of coagulation caused by deficiency of factor VIII (FVIII). The mainstay of treatment has been replacement therapy with recombinant human FVIII. However, because of high cost, access to therapy, and inhibitory antibody formation, patients continue to suffer from significant long-term morbidity and mortality. The overall goal of this application is to establish the safe and effective HA gene therapy with helper-dependent adenovirus vector which, when combined with novel physical interventions (such as hemofiltration) that can be readily translated in the clinical arena for future clinical trials.
|Suzuki, Masataka (2017) Partners in Crime: Combining Oncolytic Viroimmunotherapy with Other Therapies. Mol Ther 25:836-838|
|Tanoue, Kiyonori; Rosewell Shaw, Amanda; Watanabe, Norihiro et al. (2017) Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors. Cancer Res 77:2040-2051|
|Rosewell Shaw, Amanda; Suzuki, Masataka (2016) Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol 21:9-15|
|Rajagopal, Abbhirami; Homan, Erica P; Joeng, Kyu Sang et al. (2016) Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice. Mol Genet Metab 117:378-82|
|Hoyos, Valentina; Del Bufalo, Francesca; Yagyu, Shigeki et al. (2015) Mesenchymal Stromal Cells for Linked Delivery of Oncolytic and Apoptotic Adenoviruses to Non-small-cell Lung Cancers. Mol Ther 23:1497-506|
|Rogers, Geoffrey L; Suzuki, Masataka; Zolotukhin, Irene et al. (2015) Unique Roles of TLR9- and MyD88-Dependent and -Independent Pathways in Adaptive Immune Responses to AAV-Mediated Gene Transfer. J Innate Immun 7:302-14|
|Farzad, Lisa; Cerullo, Vincenzo; Yagyu, Shigeki et al. (2014) Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy. Mol Ther Oncolytics 1:14008|
|Suzuki, Masataka; Bertin, Terry K; Rogers, Geoffrey L et al. (2013) Differential type I interferon-dependent transgene silencing of helper-dependent adenoviral vs. adeno-associated viral vectors in vivo. Mol Ther 21:796-805|
|Guse, Kilian; Suzuki, Masataka; Sule, Gautam et al. (2012) Capsid-modified adenoviral vectors for improved muscle-directed gene therapy. Hum Gene Ther 23:1065-70|
|Sule, Gautam; Suzuki, Masataka; Guse, Kilian et al. (2012) Cytokine-conditioned dendritic cells induce humoral tolerance to protein therapy in mice. Hum Gene Ther 23:769-80|
Showing the most recent 10 out of 15 publications