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Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia.
Med J Aust. 2005 May 02; 182(9):458-63.MJ

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.

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.

Authors+Show Affiliations

Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Unit, Sydney, NSW.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15865589

Citation

Ginn, Samantha L., et al. "Treatment of an Infant With X-linked Severe Combined Immunodeficiency (SCID-X1) By Gene Therapy in Australia." The Medical Journal of Australia, vol. 182, no. 9, 2005, pp. 458-63.
Ginn SL, Curtin JA, Kramer B, et al. Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia. Med J Aust. 2005;182(9):458-63.
Ginn, S. L., Curtin, J. A., Kramer, B., Smyth, C. M., Wong, M., Kakakios, A., McCowage, G. B., Watson, D., Alexander, S. I., Latham, M., Cunningham, S. C., Zheng, M., Hobson, L., Rowe, P. B., Fischer, A., Cavazzana-Calvo, M., Hacein-Bey-Abina, S., & Alexander, I. E. (2005). Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia. The Medical Journal of Australia, 182(9), 458-63.
Ginn SL, et al. Treatment of an Infant With X-linked Severe Combined Immunodeficiency (SCID-X1) By Gene Therapy in Australia. Med J Aust. 2005 May 2;182(9):458-63. PubMed PMID: 15865589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Treatment of an infant with X-linked severe combined immunodeficiency (SCID-X1) by gene therapy in Australia. AU - Ginn,Samantha L, AU - Curtin,Julie A, AU - Kramer,Belinda, AU - Smyth,Christine M, AU - Wong,Melanie, AU - Kakakios,Alyson, AU - McCowage,Geoffrey B, AU - Watson,Debbie, AU - Alexander,Stephen I, AU - Latham,Margot, AU - Cunningham,Sharon C, AU - Zheng,Maolin, AU - Hobson,Linda, AU - Rowe,Peter B, AU - Fischer,Alain, AU - Cavazzana-Calvo,Marina, AU - Hacein-Bey-Abina,Salima, AU - Alexander,Ian E, PY - 2004/11/26/received PY - 2005/03/08/accepted PY - 2005/5/4/pubmed PY - 2005/7/16/medline PY - 2005/5/4/entrez SP - 458 EP - 63 JF - The Medical journal of Australia JO - Med. J. Aust. VL - 182 IS - 9 N2 - 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. SN - 0025-729X UR - https://www.unboundmedicine.com/medline/citation/15865589/Treatment_of_an_infant_with_X_linked_severe_combined_immunodeficiency__SCID_X1__by_gene_therapy_in_Australia_ L2 - https://www.mja.com.au/public/issues/182_09_020505/gin10862_fm.html DB - PRIME DP - Unbound Medicine ER -