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. DESIGN AND SETTING: 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. PATIENT: 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. PROCEDURE: 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.
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. DESIGN AND SETTING: 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. PATIENT: 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. PROCEDURE: 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 humangamma 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: Salima Hacein-Bey-Abina; Julia Hauer; Annick Lim; Capucine Picard; Gary P Wang; Charles C Berry; Chantal Martinache; Frédéric Rieux-Laucat; Sylvain Latour; Bernd H Belohradsky; Lily Leiva; Ricardo Sorensen; Marianne Debré; Jean Laurent Casanova; Stephane Blanche; Anne Durandy; Frederic D Bushman; Alain Fischer; Marina Cavazzana-Calvo Journal: N Engl J Med Date: 2010-07-22 Impact factor: 91.245
Authors: Douglas R Kennedy; Kyle McLellan; Peter F Moore; Paula S Henthorn; Peter J Felsburg Journal: Biol Blood Marrow Transplant Date: 2009-06 Impact factor: 5.742
Authors: Claus V Hallwirth; Gagan Garg; Timothy J Peters; Belinda A Kramer; Nirav V Malani; Jessica Hyman; Xiaoan Ruan; Samantha L Ginn; Nicola A Hetherington; Lavanya Veeravalli; Atif Shahab; Shoba Ranganathan; Chia-Lin Wei; Christopher Liddle; Adrian J Thrasher; Frederic D Bushman; Michael J Buckley; Ian E Alexander Journal: Mol Ther Methods Clin Dev Date: 2015-04-29 Impact factor: 6.698
Authors: Elnaz Farahbakhshian; Monique M Verstegen; Trudi P Visser; Sima Kheradmandkia; Dirk Geerts; Shazia Arshad; Noveen Riaz; Frank Grosveld; Niek P van Til; Jules P P Meijerink Journal: PLoS One Date: 2014-08-29 Impact factor: 3.240