X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-β region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design.

/pdf/insertional-mutagenesis-combined-with-acquired-somatic-f1kwdpvk87.pdf

Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients

Background We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxificati...

/pdf/gene-therapy-for-immunodeficiency-due-to-adenosine-deaminase-40nvjk0cqr.pdf

Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future.

Gene therapy clinical trials worldwide to 2012 - an update

Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.

/pdf/genomic-instability-and-myelodysplasia-with-monosomy-7-1gdj909aps.pdf

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

To date, over 1340 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. In 1997 we set up a database to bring together global information on gene therapy clinical trials as comprehensively as possible. The data are compiled and regularly updated from official agency sources, published literature, conference presentations and posters and from information kindly provided by investigators or trial sponsors themselves.



This review updates our descriptive overview of the data in 2004 1, presenting our analysis of the clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of July 30 2007, we have stored entries on 1309 trials in 28 countries. We have analyzed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our interactive, searchable database can be found on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. Copyright © 2007 John Wiley & Sons, Ltd.

/pdf/gene-therapy-clinical-trials-worldwide-to-2007-an-update-2ihycti29m.pdf

Gene therapy clinical trials worldwide to 2007--an update.

Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning.

Long term intravenous immunoglobulin (IVIG) infusion is an effective treatment for children with immunodeficiencies, but can be complicated by poor venous access, systemic adverse reactions, and the need for frequent hospital admission. Rapid subcutaneous immunoglobulin (SCIG) infusion has been found to be effective in adults with primary immunodeficiency. Twenty six children were treated with SCIG for a median period of two years (range six months to 3.5 years). Fifteen children had previously been treated with IVIG. Retrospective analysis showed that trough IgG concentrations while receiving SCIG were comparable with those while receiving IVIG during maintenance treatment. In severe hypogammaglobulinaemia, however, initial loading with SCIG or IVIG is probably indicated. During the treatment period there was no systemic adverse reaction nor severe reaction requiring admission to hospital. The subjective impression of all families was a significant improvement in the quality of life. This preliminary experience with SCIG in children suggests that it is an effective, convenient, and well tolerated alternative to intravenous treatment. Larger prospective studies are required to determine the place of SCIG in the management of immunodeficiencies.

https://adc.bmj.com/content/archdischild/79/1/48.full.pdf

Immunoglobulin replacement treatment by rapid subcutaneous infusion

Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies

Haematopoietic stem cell transplantation (HSCT) is a highly successful treatment for severe congenital immunodeficiencies. However, some studies have suggested that children may experience cognitive difficulties following HSCT. This large scale study assessed cognitive and behavioural function for the cohort of children treated by HSCT at one centre between 1979 - 2003 to determine the frequency and severity of problems and to identify risk factors. 105 patients were assessed on standardized measures of cognitive and emotional and behavioural function together with a control group of unaffected siblings. The average IQ for the cohort was 85 (95 percent confidence interval 81 - 90), significantly lower than both the population average of 100 (p<0.001) and unaffected siblings. Multivariate analysis indicated that the underlying genetic defect, diagnosis of ADA deficient severe combined immunodeficiency and consanguinity were associated with worse outcome, but that age at transplant and chemotherapy conditioning were not. Children treated by HSCT for severe immunodeficiency have an increased risk of long term cognitive difficulties and associated emotional and behavioural difficulties. The specific genetic diagnosis, consanguinity and severe clinical course are associated with poor outcome. Long term follow up of these patients should include screening to identify and manage these problems more effectively. From bloodjournal.hematologylibrary.org by guest on June 12, 2013. For personal use only.

Jane Gaspar

Papers

Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning.

Immunoglobulin replacement treatment by rapid subcutaneous infusion

Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies

immunodeficiencies haematopoietic stem cell transplantation for severe congenital Cognitive and behavioural abnormalities in children following