Transient Immunosuppression Allows Transgene Expression Following Readministration of Adeno-Associated Viral Vectors

Abstract

Adeno-associated viral (AAV) vectors have much promise in gene therapy. Among the many properties that make AAV an ideal vector for gene therapy are its ability to infect both dividing and nondividing cells and the longevity of expression in tissues such as brain, skeletal muscle, and liver. However, like other viral vectors, readministration of vector is limited because of the host's immune response to viral components of the vector. Using class I, class II, and CD40 ligand (CD40L)-deficient mice, we demonstrate that neutralizing antibodies to the viral capsid proteins prevent transgene expression following readministration of rAAV vectors. Transient immunosuppression of mice by treatment with antibody to CD4 at the time of primary infection allowed transgene expression after readministration of rAAV vectors to animals. Transient immunosuppression with antibody to CD40L had only a modest effect on the efficacy of readministration. The ability to readminister virus was inversely correlated with both AAV capsid enzyme-linked immunosorbent assay titers and AAV neutralizing antibody titers. These studies demonstrate that readministration of rAAV can be accomplished by down regulating the anti-AAV immune response and suggest the use of repeated administration of rAAV as a viable form of therapy for the treatment of chronic diseases. A problem common to all viral vectors in gene therapy is that the host can mount an immune response to the vector. This immune response prevents transgene expression following readministration of the viral vector. Our results show that the host's humoral immune response prevents intramuscular readministration of adeno-associated viral (AAV) vectors. By transiently immunosuppressing mice at the time of first administration with antibody to CD4, we show that readministration of rAAV vectors is possible.