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Intramuscular administration of AAV overcomes pre-existing neutralizing antibodies in rhesus macaques.
Greig, Jenny A; Calcedo, Roberto; Grant, Rebecca L; Peng, Hui; Medina-Jaszek, C Angelica; Ahonkhai, Omua; Qin, Qiuyue; Roy, Soumitra; Tretiakova, Anna P; Wilson, James M.
Afiliación
  • Greig JA; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Calcedo R; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Grant RL; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Peng H; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Medina-Jaszek CA; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Ahonkhai O; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Qin Q; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Roy S; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Tretiakova AP; Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA.
  • Wilson JM; 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.
Vaccine ; 34(50): 6323-6329, 2016 12 07.
Article en En | MEDLINE | ID: mdl-27817961
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dependovirus / Anticuerpos Neutralizantes / Vectores Genéticos / Anticuerpos Antivirales Límite: Animals Idioma: En Revista: Vaccine Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dependovirus / Anticuerpos Neutralizantes / Vectores Genéticos / Anticuerpos Antivirales Límite: Animals Idioma: En Revista: Vaccine Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos