Failure of SCID-X1 gene therapy in older patients.
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.
- SourceAvailable from: Claudia R Ball[Show abstract] [Hide abstract]
ABSTRACT: Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.Science translational medicine 03/2014; 6(227):227ra33. · 14.41 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Thirty years ago, retroviral transfer of genetic material into hematopoietic stem and progenitor cells (HSC/Ps) led to predictions that this technology would transform modern medicine [Nature 1983;305:556-558; Nature 1984;310:476-480]. Studies studies in several immunodeficiency diseases in the past 15 years have demonstrated clear proof of principle that gene therapy can have long-lasting, potentially curative effects without the need to search for allogeneic donors and without risk of graft-versus-host disease. Improvement in gene transfer efficiency for target HSC/Ps brought to light issues of insertional mutagenesis caused by transfer vectors, resulting in oncogene transactivation and leukemias. Lessons from these adverse events have now led to a new generation of vectors, refinements in conditioning regimens, and manufacturing, which are paving the way for expanded applications of the current technology and recent emphasis on gene targeting/genome editing as the next advancements in the field.STEM CELLS TRANSLATIONAL MEDICINE 03/2014; · 3.60 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Introduction: During the last decade, gene therapy has emerged as a convincing therapy for primary immunodeficiencies (PIDs). Ex vivo gene transfer into autologous hematopoietic stem cells (HSCs) via viral vectors permits sustained correction of T cell immunodeficiency in two forms of severe combined immunodeficiency: X-linked SCID (SCID-X1) (γ chain [γc] deficiency) and adenosine deaminase deficiency. However, this success has been balanced by the occurrence of genotoxicity generated by the integration of first-generation retroviral vectors. Recently, the development of safer self-inactivating vectors has led to the initiation of new studies with the hope of equivalent efficacy and a better safety profile. Areas covered: This review article focuses on the updated results of gene therapy trials for PIDs - from early studies to ongoing clinical trials. We detail the major advances made in gene transfer and repair technologies, and discuss the many ways to extend our present experience. Expert opinion: With optimization in terms of safety and efficacy, gene therapy by lentiviral transduction could become a compelling alternative to allogeneic HSC transplantation, and thus may take center stage in the management of PIDs in coming years.Expert opinion on biological therapy 06/2014; 14(6):789-98. · 3.22 Impact Factor