Long-term safety and efficacy of factor IX gene therapy in hemophilia B

Amit C. Nathwani, U. M. Reiss, E. G D Tuddenham, C. Rosales, P. Chowdary, J. McIntosh, M. Della Peruta, E. Lheriteau, N. Patel, D. Raj, A. Riddell, J. Pie, S. Rangarajan, D. Bevan, M. Recht, Y. M. Shen, K. G. Halka, E. Basner-Tschakarjan, F. Mingozzi, K. A. HighJ. Allay, M. A. Kay, C. Y C Ng, J. Zhou, M. Cancio, C. L. Morton, J. T. Gray, D. Srivastava, A. W. Nienhuis, A. M. Davidoff

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882 Scopus citations


BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported.

Original languageEnglish (US)
Pages (from-to)1994-2004
Number of pages11
JournalNew England Journal of Medicine
Issue number21
StatePublished - Nov 20 2014

ASJC Scopus subject areas

  • Medicine(all)


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