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.

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Available from: Christophe Hue, Mar 30, 2015
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    • "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. "
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    • "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. "
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