Adeno-associated viral (AAV) vectors are in advanced clinical development for treatment of multiple genetic diseases. Nevertheless, unexpected immune responses have substantially slowed down clinical advances, as for instance in the case of the X-linked bleeding disorder hemophilia, where activation of CD8+ T cells continues to cause complications for patients. For example, CD8+ T cells directed against AAV capsid target transduced human hepatocytes thus causing liver toxicity and loss of expression. Similarly, upon gene transfer into skeletal muscle aimed at treating a variety of genetic diseases, CD8+ T cell responses directed against capsid, and in some patients against the transgene product, were observed. These were often associated with prolonged inflammation and resulted in cytotoxicity and/or cytokine production and partial loss of expression. Another major concern for many replacement therapies is antibody formation against the transgene product, which we have extensively addressed in previous funding cycles. Our key discovery that hepatic AAV gene transfer can induce immune tolerance to the transgene product (partly through induction of regulatory T cell, Treg) facilitated the establishment of effective clinical gene therapies for hemophilia, as well as the pre-clinical development of immune modulatory gene therapies for multiple diseases. We have since established several alternative methods to prevent or reverse antibody formation against therapeutic proteins. Because of the clinical observations summarized above, we are now performing in-depth studies on the mechanism of CD8+ T cell activation in AAV gene transfer. We have also identified novel approaches to prevent such responses by blocking require innate immune signals. To address major gaps in knowledge on CD8+ T cell activation in response to AAV and to reduce immunogenicity of AAV gene transfer, we propose to define the mechanism of dendritic cell licensing in AAV gene transfer; to define the mechanisms that lead to transgene product-specific CD8+ T cell responses; and to develop innate immune blockade to prevent CD8+ T cell activation upon AAV- FIX gene transfer.

Public Health Relevance

Gene therapy for the inherited bleeding disorder hemophilia has now been successful in patients, representing a cure rather than merely treatment of the disease. However, the immune system may reject the gene medicine, which has also been a problem in other diseases. The proposal seeks to prevent such immune responses, so that patients receive lasting therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051390-19
Application #
9600642
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Voulgaropoulou, Frosso
Project Start
2002-04-01
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Biswas, Moanaro; Kumar, Sandeep R P; Terhorst, Cox et al. (2018) Gene Therapy With Regulatory T Cells: A Beneficial Alliance. Front Immunol 9:554
Herzog, Roland W; Cooper, Mario; Perrin, George Q et al. (2017) Regulatory T cells and TLR9 activation shape antibody formation to a secreted transgene product in AAV muscle gene transfer. Cell Immunol :
Biswas, Moanaro; Rogers, Geoffrey L; Sherman, Alexandra et al. (2017) Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin. Thromb Haemost 117:33-43
Rogers, Geoffrey L; Shirley, Jamie L; Zolotukhin, Irene et al. (2017) Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8+ T cells. Blood 129:3184-3195
Wang, Xiaomei; Herzog, Roland W; Byrne, Barry J et al. (2017) Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells. Mol Ther Methods Clin Dev 5:76-82
Kumar, Sandeep R P; Hoffman, Brad E; Terhorst, Cox et al. (2017) The Balance between CD8+ T Cell-Mediated Clearance of AAV-Encoded Antigen in the Liver and Tolerance Is Dependent on the Vector Dose. Mol Ther 25:880-891
Herzog, Roland W (2017) Complexity of immune responses to AAV transgene products - Example of factor IX. Cell Immunol :
Palaschak, Brett; Marsic, Damien; Herzog, Roland W et al. (2017) An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells. Mol Ther Methods Clin Dev 5:142-152
Sherman, Alexandra; Biswas, Moanaro; Herzog, Roland W (2017) Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A. Front Immunol 8:1604
Markusic, David M; Nichols, Timothy C; Merricks, Elizabeth P et al. (2017) Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models. J Transl Med 15:94

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