Failure of SCID-X1 gene therapy in older patients

Molecular Immunology Unit, Institute of Child Health, London, United Kingdom.
Blood (Impact Factor: 10.45). 07/2005; 105(11):4255-7. DOI: 10.1182/blood-2004-12-4837
Source: PubMed


Gene therapy has been shown to be a highly effective treatment for infants with typical X-linked severe combined immunodeficiency (SCID-X1, gammac-deficiency). For patients in whom previous allogeneic transplantation has failed, and others with attenuated disease who may present later in life, the optimal treatment strategy in the absence of human leukocyte antigen (HLA)-matched donors is unclear. Here we report the failure of gene therapy in 2 such patients, despite effective gene transfer to bone marrow CD34(+) cells, suggesting that there are intrinsic host-dependent restrictions to efficacy. In particular, there is likely to be a limitation to initiation of normal thymopoiesis, and we therefore suggest that intervention for these patients should be considered as early as possible.

Download full-text


Available from: Christophe Hue, Mar 30, 2015
12 Reads
  • Source
    • "Definition of the window within which gene therapy will be effective is therefore vitally important, as suggested for other more conventional therapeutic modalities [26]. This 459 GENE THERAPY FOR PRIMARY IMMUNODEFICIENCIES necessity has been clearly demonstrated by the failure of immunologic reconstitution in several older patients following effective gene transfer to bone marrow or peripheral blood CD34þ cells [23] [27]. At least for SCID, it is likely that host-related restrictions to efficacy exist, for example because of the inability to initiate or reinitiate an exhausted or failed program of thymopoiesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs.
    Human gene therapy 06/2012; 23(7):668-75. DOI:10.1089/hum.2012.116 · 3.76 Impact Factor
  • Source
    • "To date more than 20 X- SCID patients have received ex vivo gene therapy with a gammaretroviral vector containing IL2RG (Fischer and Cavazzana-Calvo 2008). However, treatment of older patients has not been successful, possibly due to the role of thymopoiesis in early childhood (Thrasher et al. 2005). In contrast to HSCT, gene therapy has restored sufficient B cell function in most X- SCID patients to allow cessation of IVIG administration. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic mutations involving the cellular components of the hematopoietic system--red blood cells, white blood cells, and platelets--manifest clinically as anemia, infection, and bleeding. Although gene targeting has recapitulated many of these diseases in mice, these murine homologues are limited as translational models by their small size and brief life span as well as the fact that mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of such mutations in humans. Many of these limitations can be overcome by identifying large animals with genetic diseases of the hematopoietic system corresponding to their human disease counterparts. In this article, we describe human diseases of the cellular components of the hematopoietic system that have counterparts in large animal species, in most cases carrying mutations in the same gene (CD18 in leukocyte adhesion deficiency) or genes in interacting proteins (DNA cross-link repair 1C protein and protein kinase, DNA-activated catalytic polypeptide in radiation-sensitive severe combined immunodeficiency). Furthermore, we describe the potential of these animal models to serve as disease-specific preclinical models for testing the efficacy and safety of clinical interventions such as hematopoietic stem cell transplantation or gene therapy before their use in humans with the corresponding disease.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 02/2009; 50(2):168-86. DOI:10.1093/ilar.50.2.168 · 2.39 Impact Factor
  • Medecine sciences: M/S 23(8-9):690-1. DOI:10.1051/medsci/20072389690 · 0.67 Impact Factor
Show more