Enhanced Factor IX Activity following Administration of AAV5-R338L "Padua" Factor IX versus AAV5 WT Human Factor IX in NHPs.

Autor:	Spronck EA; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Liu YP; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Lubelski J; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Ehlert E; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Gielen S; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Montenegro-Miranda P; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., de Haan M; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Nijmeijer B; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Ferreira V; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., Petry H; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands., van Deventer SJ; uniQure biopharma B.V., Paasheuvelweg 25A, 1105 BP Amsterdam, the Netherlands.; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2019 Sep 26; Vol. 15, pp. 221-231. Date of Electronic Publication: 2019 Sep 26 (Print Publication: 2019).
DOI:	10.1016/j.omtm.2019.09.005
Abstrakt:	Gene therapy for severe hemophilia B is advancing and offers sustained disease amelioration with a single treatment. We have reported the efficacy and safety of AMT-060, an investigational gene therapy comprising an adeno-associated virus serotype 5 capsid encapsidating the codon-optimized wild-type human factor IX (WT h FIX ) gene with a liver-specific promoter, in patients with severe hemophilia B. Treatment with 2 × 10 13 gc/kg AMT-060 showed sustained and durable FIX activity of 3%-13% and a substantial reduction in spontaneous bleeds without T cell-mediated hepatoxicity. To achieve higher FIX activity, we modified AMT-060 to encode the R338L "Padua" FIX variant that has increased specific activity (AMT-061). We report the safety and increased FIX activity of AMT-061 in non-human primates. Animals (n = 3/group) received intravenous AMT-060 (5 × 10 12 gc/kg), AMT-061 (ranging from 5 × 10 11 to 9 × 10 13 gc/kg), or vehicle. Human FIX protein expression, FIX activity, and coagulation markers including D-dimer and thrombin-antithrombin complexes were measured. At equal doses, AMT-060 and AMT-061 resulted in similar human FIX protein expression, but FIX activity was 6.5-fold enhanced using AMT-061. Both vectors show similar safety and transduction profiles. Thus, AMT-061 holds great promise as a more potent FIX replacement gene therapy with a favorable safety profile. (© 2019 The Authors.)
Databáze:	MEDLINE
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