title: Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B.
abstract: Liver gene transfer for hemophilia B has shown very promising results in recent clinical studies. A potential complication of gene-based treatments for hemophilia and other inherited disorders, however, is the development of neutralizing antibodies (NAb) against the therapeutic transgene. The risk of developing NAb to the coagulation factor IX (F.IX) transgene product following adeno-associated virus (AAV)-mediated hepatic gene transfer for hemophilia is small but not absent, as formation of inhibitory antibodies to F.IX is observed in experimental animals following liver gene transfer. Thus, strategies to modulate antitransgene NAb responses are needed. Here, we used the anti-B cell monoclonal antibody rituximab (rtx) in combination with cyclosporine A (CsA) to eradicate anti-human F.IX NAb in rhesus macaques previously injected intravenously with AAV8 vectors expressing human F.IX. A short course of immunosuppression (IS) resulted in eradication of anti-F.IX NAb with restoration of plasma F.IX transgene product detection. In one animal, following IS anti-AAV6 antibodies also dropped below detection, allowing for successful AAV vector readministration and resulting in high levels (60% or normal) of F.IX transgene product in plasma. Though the number of animals is small, this study supports for the safety and efficacy of B cell-targeting therapies to eradicate NAb developed following AAV-mediated gene transfer.
authors.affiliation: Division of Hematology, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. mingozzi@email.chop.edu
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Murphy
authors.forename: Shyrie C
authors.initials: SC
authors.lastname: Edmonson
authors.forename: Alex
authors.initials: A
authors.lastname: Tai
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Price
authors.forename: Mark E
authors.initials: ME
authors.lastname: Metzger
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.forename: Robert E
authors.initials: RE
authors.lastname: Donahue
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003524:Cyclosporins / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics; D005164:Factor IX / Q000235:genetics / Q000276:immunology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy*; D056724:Immunity, Humoral / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008253:Macaca mulatta; D000069283:Rituximab; D019076:Transgenes
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D003524:Cyclosporins; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069283:Rituximab; D005164:Factor IX