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

Jun 30, 2015 | Magazine: Gene Therapy

Unzu C(1), Melero I(2), Hervás-Stubbs S(3), Sampedro A(1), Mancheño U(1), Morales-Kastresana A(1), Serrano-Mendioroz I(1), de Salamanca RE(4), Benito A(5), Fontanellas A(6).

Abstract

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 the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 1012 viral particles/kg (1010 infective units/kg) of HDA only resulted in transient (≈14 weeks) transgene-expression in one out of three individuals.

In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene-expression under immunosuppression reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. Immunosuppression controlled anti-capsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene-expression only in those animals receiving immunosuppression again at the time of this second vector exposure.

Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological immunosuppression.Gene Therapy accepted article preview online, 30 June 2015. doi:10.1038/gt.2015.64.

CITATION Gene Ther. 2015 Jun 30. doi: 10.1038/gt.2015.64.

see publication in pubmed