par Nair, Nisha;Rincón, Melvin Yesid;Evens, Hanneke;Sarcar, Shilpita;Dastidar, Sumitava;Samara-Kuko, Ermira;Ghandeharian, Omid 
;Viecelli, Hiu Man;Thöny, Beat;De Bleser, Pieter;VandenDriessche, Thierry;Chuah Lay Khim, Marinee
Référence Blood, 123, 20, page (3195-3199)
Publication Publié, 2014-05
;Viecelli, Hiu Man;Thöny, Beat;De Bleser, Pieter;VandenDriessche, Thierry;Chuah Lay Khim, Marinee Référence Blood, 123, 20, page (3195-3199)
Publication Publié, 2014-05
Article révisé par les pairs
| Résumé : | The development of the next-generation gene therapy vectors for hemophilia requires using lower and thus potentially safer vector doses and augmenting their therapeutic efficacy. We have identified hepatocyte-specific transcriptional cis-regulatory modules (CRMs) by using a computational strategy that increased factor IX (FIX) levels 11- to 15-fold. Vector efficacy could be enhanced by combining these hepatocyte-specific CRMs with a synthetic codon-optimized hyperfunctional FIX-R338L Padua transgene. This Padua mutation boosted FIX activity up to sevenfold, with no apparent increase in thrombotic risk. We then validated this combination approach using self-complementary adenoassociated virus serotype 9 (scAAV9) vectors inhemophiliaBmice. This resulted in sustained supraphysiologic FIX activity (400%), correction of the bleeding diathesis at clinically relevant, low vector doses (5×10 10 vector genomes[vg]/kg) that are considered safe in patients undergoing gene therapy. Moreover, immune tolerance could be induced that precluded induction of inhibitory antibodies to FIX upon immunization with recombinant FIX protein. © 2014 by The American Society of Hematology. |
