Article

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

ABSTRACT

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

Full-text

Available from: Christophe Hue, Mar 30, 2015
  • 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.
    Full-text · Article · Jun 2012 · Human gene therapy
  • 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.
    Preview · Article · Feb 2009 · ILAR journal / National Research Council, Institute of Laboratory Animal Resources
  • [Show abstract] [Hide abstract]
    ABSTRACT: Over the past decades, gene therapy as a tool to cure disease has blossomed into an exciting clinical possibility. Gene transfer technologies have progressed immensely since the field’s inception (Figure 45.1). The first replication-defective retroviral vector was described in 1983, and by 1990 clinical studies using retroviral vectors began. Although initial efforts were robust, by 1996, none of the clinical gene “therapy” trials had shown clinical efficacy. After a change in policy and focus instituted by a panel convened by the National Institutes of Health, efforts to develop gene transfer technologies shifted toward targeting diseases that were early and obvious targets for therapeutic intervention. The simultaneous experimental advances in our understanding of hematopoiesis and the significant advances in gene transfer technology have led to success in humans, at least for disorders requiring modest transfer rates of genes not requiring complex regulation to hematopoietic stem cell (HSC) targets.
    No preview · Article ·
Show more