title: Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia.
abstract: OBJECTIVE
  To report the outcome of gene therapy in an infant with X-linked severe combined immunodeficiency (SCID-X1), which typically causes a lack of T and natural killer (NK) cells.
  
  
  METHODS
  Ex-vivo culture and gene transfer procedures were performed at The Children's Hospital at Westmead, Sydney, NSW, in March 2002. Follow-up to March 2005 (36 months) is available.
  
  
  METHODS
  A 9-month-old male infant with confirmed SCID-X1 (including complete absence of T cells) with an NK+ phenotype (a less common variant of SCID-X1), and no HLA-identical sibling donor available for conventional bone marrow transplantation.
  
  
  METHODS
  CD34+ haemopoietic progenitor cells were isolated from harvested bone marrow and cultured with cytokines to stimulate cellular replication. Cells were then genetically modified by exposure to a retrovirus vector encoding human gamma c (the common gamma chain of several interleukin receptors; mutations affecting the gamma c gene cause SCID-X1). Gene-modified cells (equivalent to 1.3 x 10(6) CD34+/gamma c+ cells/kg) were returned to the infant via a central line.
  
  
  RESULTS
  T cells were observed in peripheral blood 75 days after treatment, and levels increased rapidly to 0.46 x 10(9) CD3+ cells/L at 5 months. Within 2 weeks of the appearance of T cells, there was a distinct clinical improvement, with early weight gain and clearance of rotavirus from the gut. However, T-cell levels did not reach the reference range, and immune reconstitution remained incomplete. The infant failed to thrive and developed weakness, hypertonia and hyperreflexia in the legs, possibly the result of immune dysregulation. He went on to receive a bone marrow transplant from a matched unrelated donor 26 months after gene therapy.
  
  
  CONCLUSIONS
  This is the first occasion that gene therapy has been used to treat a genetic disease in Australia. Only partial immunological reconstitution was achieved, most likely because of the relatively low dose of gene-corrected CD34+ cells re-infused, although viral infection during the early phase of T-cell reconstitution and the infant's NK+ phenotype may also have exerted an effect.
authors.affiliation: Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Unit, Sydney, NSW.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Ginn
authors.forename: Julie A
authors.initials: JA
authors.lastname: Curtin
authors.forename: Belinda
authors.initials: B
authors.lastname: Kramer
authors.forename: Christine M
authors.initials: CM
authors.lastname: Smyth
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Alyson
authors.initials: A
authors.lastname: Kakakios
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: McCowage
authors.forename: Debbie
authors.initials: D
authors.lastname: Watson
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Margot
authors.initials: M
authors.lastname: Latham
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Cunningham
authors.forename: Maolin
authors.initials: M
authors.lastname: Zheng
authors.forename: Linda
authors.initials: L
authors.lastname: Hobson
authors.forename: Peter B
authors.initials: PB
authors.lastname: Rowe
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander
mesh_terms: D018952:Antigens, CD34; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy*; D016176:T-Lymphocyte Subsets; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34