title: Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.
abstract: BACKGROUND
  Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder.
  
  
  METHODS
  We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months.
  
  
  RESULTS
  AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.
  
  
  CONCLUSIONS
  Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.).
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom. a.nathwani@ucl.ac.uk
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
authors.forename: Edward G D
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authors.forename: Arnulfo Jaquilmac
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authors.lastname: Pie
authors.forename: Chris
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authors.lastname: Harrington
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authors.lastname: Smith
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authors.lastname: Glader
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authors.forename: Catherine Y C
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authors.lastname: Ng
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kay
authors.forename: Junfang
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authors.lastname: Zhou
authors.forename: Yunyu
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authors.lastname: Spence
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: James
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authors.lastname: Allay
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authors.lastname: Coleman
authors.forename: Susan
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authors.lastname: Sleep
authors.forename: John M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Deokumar
authors.initials: D
authors.lastname: Srivastava
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: John T
authors.initials: JT
authors.lastname: Gray
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Reiss
authors.forename: Arthur W
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authors.lastname: Nienhuis
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D000328:Adult; D000229:Dependovirus / Q000235:genetics; D005164:Factor IX / Q000235:genetics* / Q000627:therapeutic use; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000276:immunology; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D019076:Transgenes / Q000276:immunology
chemical_list: D005164:Factor IX