title: Long-term safety and efficacy of factor IX gene therapy in hemophilia B.
abstract: 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 (2×10(12) 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. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
authors.forename: Ulreke M
authors.initials: UM
authors.lastname: Reiss
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rosales
authors.forename: Pratima
authors.initials: P
authors.lastname: Chowdary
authors.forename: Jenny
authors.initials: J
authors.lastname: McIntosh
authors.forename: Marco
authors.initials: M
authors.lastname: Della Peruta
authors.forename: Elsa
authors.initials: E
authors.lastname: Lheriteau
authors.forename: Nishal
authors.initials: N
authors.lastname: Patel
authors.forename: Deepak
authors.initials: D
authors.lastname: Raj
authors.forename: Anne
authors.initials: A
authors.lastname: Riddell
authors.forename: Jun
authors.initials: J
authors.lastname: Pie
authors.forename: Savita
authors.initials: S
authors.lastname: Rangarajan
authors.forename: David
authors.initials: D
authors.lastname: Bevan
authors.forename: Michael
authors.initials: M
authors.lastname: Recht
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Shen
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Halka
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.forename: James
authors.initials: J
authors.lastname: Allay
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kay
authors.forename: Catherine Y C
authors.initials: CY
authors.lastname: Ng
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhou
authors.forename: Maria
authors.initials: M
authors.lastname: Cancio
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: John T
authors.initials: JT
authors.lastname: Gray
authors.forename: Deokumar
authors.initials: D
authors.lastname: Srivastava
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Nienhuis
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000229:Dependovirus / Q000235:genetics; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D005500:Follow-Up Studies; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000008:administration & dosage*; D002836:Hemophilia B / Q000097:blood / Q000235:genetics / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D019076:Transgenes; D055815:Young Adult
chemical_list: D005164:Factor IX; D000410:Alanine Transaminase