Treatment of an infant with X‐linked severe combined immunodeficiency (SCID‐X1) by gene therapy in Australia

• Published in: Medical journal of Australia 2005-05, Vol.182 (9), p.458-463
• Main Authors: Ginn, Samantha L, Curtin, Julie A, Smyth, Christine M, Latham, Margot, Cunningham, Sharon C, Zheng, Maolin, Hobson, Linda, Rowe, Peter B, Alexander, Ian E, Kramer, Belinda, Wong, Melanie, Kakakios, Alyson, McCowage, Geoffrey B, Watson, Debbie, Alexander, Stephen I, Fischer, Alain, Cavazzana‐Calvo, Marina, Hacein‐Bey‐Abina, Salima
• Format: Article
• Language: English
• Subjects: Antigens; Antigens, CD34; Babies; Biological and medical sciences; Blood; Bone marrow; Cell growth; Children & youth; Cytokines; Families & family life; Gene therapy; Gene Transfer Techniques; General aspects; Genetic Therapy - methods; Genetic Vectors; Genotype & phenotype; Hematopoietic Stem Cells - immunology; Humans; Immune system; Immune system diseases; Immunoglobulins; Immunology; Infant; Killer Cells, Natural - immunology; Leukemia; Lymphocyte Count; Lymphocytes; Male; Medical genetics; Medical sciences; Mutation; Pediatric medicine; Phenotype; Rotavirus; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - therapy; Stem cell transplantation; T-Lymphocyte Subsets; Treatment Outcome; Viral infections; Viruses
• ISSN: 0025-729X; 1326-5377
• DOI: 10.5694/j.1326-5377.2005.tb06785.x

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 γc (the common γ chain of several interleukin receptors; mutations affecting the γc gene cause SCID‐X1). Gene‐modified cells (equivalent to 1.3 × 106 CD34+/γc+ 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 × 109 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.