Computationally designed liver-specific transcriptional cis-regulatory modules and hyper-functional factor IX improve liver-targeted gene therapy for hemophilia B.

Nisha Nair Shivsankaran Nair, M.y. Rincon, Hanneke Evens, Shilpita Sarcar, Sumitava Dastidar, Ermira Samara, O. Ghandeharian, H. Viecelli, B. Thony, Pieter De Bleser, Thierry VandenDriessche, Marinee Chuah

Onderzoeksoutput: Articlepeer review

65 Citaten (Scopus)

Samenvatting

The development of the next-generation gene therapy vectors for hemophilia requires the use of lower and thus potentially safer vector doses, while augmenting their therapeutic efficacy. We have identified hepatocyte-specific transcriptional cis-regulatory modules (CRMs) 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 hyper-functional FIX-R338L Padua transgene. This Padua mutation boosted FIX activity up to 7-fold, with no apparent increase in thrombotic risk. We then validated this combination approach using self-complementary serotype 9 adeno-associated viral vectors (scAAV9) in hemophilia B mice. This resulted in sustained supra-physiologic FIX activity (400%), correction of the bleeding diathesis at clinically relevant, low vector doses (5x1010 vg/kg) that are considered safe in subjects undergoing gene therapy. Moreover, immune tolerance could be induced that precluded induction of inhibitory antibodies to FIX upon immunization with recombinant FIX protein.
Originele taal-2English
Pagina's (van-tot)3195-3199
Aantal pagina's5
TijdschriftBlood
Volume123
Nummer van het tijdschrift20
StatusPublished - 2014

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