Transient immunosuppression allows transgene expression following readministration of adeno-associated viral vectors.
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.
Manning
W C
WC
Chiron Corporation, Emeryville, CA 94608, USA.
Zhou
S
S
Bland
M P
MP
Escobedo
J A
JA
Dwarki
V
V
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D000914:Antibodies, Viral / Q000097:blood; D015704:CD4 Antigens / Q000276:immunology; D023201:CD40 Ligand; D002213:Capsid / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007165:Immunosuppression Therapy; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles; D009500:Neutralization Tests; D019076:Transgenes / Q000276:immunology*
D000906:Antibodies; D000914:Antibodies, Viral; D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D008156:Luciferases