Immunization Against the Transgene but not the TetON Switch Reduces Expression From Gutless Adenoviral Vectors in the Brain

XIONG; CANDOLFI; KROEGER; PUNTEL; MONDKAR; LAROCQUE; LIU; CURTIN; PALMER; NG; LOWENSTEIN; CASTRO

MOLECULAR THERAPY (PRINT)

NATURE PUBLISHING GROUP

Año: 2008 p. 343 - 351

1525-0016

Immune responses against vectors or encoded transgenescan impose limitations on gene therapy. We demonstratedthat tetracycline-regulated high-capacity adenoviral vectors(HC-Ads) sustain regulated transgene expression in thebrain even in the presence of systemic pre-existing immuneresponses against adenoviruses. In this study we assessedwhether systemic pre-existingimmune responses againstthe transgene products, i.e., β-Galor the tetracycline-dependent(TetON) regulatory transcription factors(rtTA2SM2and the tTSKid), affect transgene expression levels and thesafety profile of HC-Ads in the brain. We pre-immunizedmice with plasmids encoding the TetON switch expressingrtTA2SM2 and the tTSKid or β-Gal.HC-Ads expressingβ-Galunder the control of the TetON switch were theninjected into the striatum.We assessed levels and distributionof β-Galexpression, and evaluated local inflammationand neuropathological changes. We found that systemicimmunity against β-Gal, but not against the TetON switch,led to inflammation and reduction of transgene expressionin the striatum. Therefore, the regulatory TetON switchappears to be safe to use, and capable of sustainingtransgeneexpression in the brain even in the presence of animmune response against its components. Systemic immunityagainst the transgene had the effect of curtailing itsexpression, thereby affecting the efficacyand safety of genedelivery to the brain. This factor should be considered whendeveloping gene therapies for neurologicaluse.