Intramuscular administration of AAV overcomes pre-existing neutralizing antibodies in rhesus macaques.
The seroprevalence of neutralizing antibodies (NAbs) to adeno-associated viral (AAV) vector capsids may preclude a percentage of the population from receiving gene therapy, particularly following systemic vector administration. We hypothesized that the use of intramuscular (IM) administration of AAV vectors might circumvent this issue. IM injections were used to administer AAV8 vectors expressing either secreted or non-secreted transgenes into mice and the influence of NAbs supplied by pre-administration of pooled human IgG on transgene expression was evaluated. We then studied the impact of naturally occurring pre-existing AAV8 NAbs on expression of a secreted transgene following IM vector delivery in rhesus macaques. Finally, we evaluated the ability to readminister AAV vectors via IM injections in rhesus macaques. In mice, the presence of AAV8 NAbs had no effect on gene expression in the injected skeletal muscle. However, liver transgene expression following hepatic distribution of the vector was ablated. In rhesus macaques, naturally occurring pre-existing AAV8 NAb titers of ⩽1:160 had no effect on expression levels of a secreted transgene after IM delivery of the vector. Additionally, readministration of AAV vectors was possible by IM injection into the previously injected muscle groups, with no effect on transgene expression by the original vector. Therefore, the presence of pre-existing NAbs in the human population should not preclude subjects from receiving gene therapy by IM administration of the vector so long as sufficient levels of secreted transgene expression can be produced without the involvement of liver.
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Jenny A
JA
Greig
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Roberto
R
Calcedo
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Rebecca L
RL
Grant
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Hui
H
Peng
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
C Angelica
CA
Medina-Jaszek
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Omua
O
Ahonkhai
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Qiuyue
Q
Qin
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Soumitra
S
Roy
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
Anna P
AP
Tretiakova
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA. Electronic address: wilsonjm@mail.med.upenn.edu.
James M
JM
Wilson
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D000229:Dependovirus / Q000276:immunology*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology*; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016036:Seroepidemiologic Studies; D019076:Transgenes
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral
AAV; Antibody; Muscle; Vector