Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.

摘要: Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with PBGD-encoding to study levels and persistence of transgene expression. Intrahepatic administration 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) only resulted transient (≈14 weeks) expression one out three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab steroids) extended meaningful over 76 weeks two cases. Transgene under immunosuppression (IS) reached maximum 6 after gradually declined reaching stable plateau within therapeutic range porphyria. The non-injected lobes also expressed because circulation. IS controlled anticapsid T-cell responses decreased induction neutralizing antibodies. Re-administration HDA-hPBGD at week +78 achieved therapeutically those animals receiving again time this second exposure. Overall, immunity against capsids poses serious hurdles long-term HDA-mediated transduction, which can be partially circumvented by pharmacological IS.