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The collaborative longitudinal personality disorders study: Reliability of axis I and II diagnoses. Journal of Personality Disorders, 14, — Download references. Thanks go to Paul Rohde, as well as the project research assistants and the participants who made this study possible. This RCT was registered on clinicaltrials. You can also search for this author in PubMed Google Scholar. Informed consent was obtained from all individual participants included in the study. All participants signed a written informed consent, as well as one of their parents.
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School Mental Health 11, — Download citation. Published : 20 March Issue Date : December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search SpringerLink Search. References Albright, L. Google Scholar Baldwin, S. Google Scholar Clarke, G. Google Scholar Dumais, A. Google Scholar First, M. The first was based on modified SIN retroviral vectors in which the enhancer regulatory sequences had been replaced by internal promoters capable of inducing limited and, in some cases, tissue-specific transcription of the therapeutic gene.
The significant reduction in these clusters suggests that SIN vectors are safer, as also confirmed by the absence of SAEs in the latest results from the corresponding clinical trials.
The second way to increase the safety of gene transfer vectors is based on HIV-derived vectors. Nevertheless, two papers show that lentiviral vector integration is responsible for an aberrantly spliced, chimeric transcript 57 and that lentiviral vectors integrate into a small chromosomal zone near the nuclear pores, 58 which further reduces the randomness of integration. It is impossible to say whether these discoveries may have clinical consequences. The tracking of integration site patterns in different settings will continue to be highly informative.
The full integrome is becoming even more accessible by the new high-throughput sequencing approaches, and ongoing developments should enable rapid access to a comprehensive integration repertoire via specific capture approaches and direct genome sequencing. We and others have shown that it is now possible to map approximately 10, RISs per patient in the new lentivirus-based gene therapy trials for WAS and metachromatic leukodystrophy. Many barcoding studies in the mouse and in the macaque have tracked various myeloid and lymphoid cell types over time and thus have generated a more precise map of the hematopoietic hierarchy.
Overall, the clonal tracking of RISs in human gene therapy trials will pave the way to a deeper understanding of human hematopoiesis. Self-inactivating vectors have formally demonstrated their improved safety profile relative to LTR-driven retroviral vectors , as no SAEs have been observed since their first use in clinical trials in Cavazzana and S. Hacein-Bey-Abina, unpublished observations. Interestingly, the abundance of this clone progressively decreased during the follow-up period.
The patient displayed a dominant clone that varied over time—albeit without any clinical impact. Given 1 the current inability to predict adverse events despite intense work on RIS analysis and 2 the absence of an accurate animal or in vitro model of toxicity, the continuous clinical follow-up of the patients is the only way to monitor the safety and efficacy of new vector designs and other technical improvements.
Another major, unresolved concern is the time needed to generate functional T cells that can successfully fight the systemic, opportunistic viral infections responsible for poor outcomes in some patients treated by gene therapy.
These precursors resemble their thymic in vivo counterparts in terms of the in vitro potential and expression profile. Because gene therapy has proved its effectiveness in several hereditary diseases of the hematopoietic system, the next major milestone will be the long-term safety of the new vectors under investigation.
Another challenge is to develop a process that can be disseminated worldwide, that is, to regions of the world where some of the hereditary diseases that might be approached by gene therapy are more prevalent. Since the first clinical trial in which we defined the whole gene therapy procedure, 78 a number of small and nonsignificant changes have been introduced into the transduction process. A technical breakthrough has been described by Verhoeyen's group.
In light of the most recent publications, it would be useful to have a culture procedure that did not require active stimulation of human HSPCs. Automation of the procedure would also constitute progress, so that any transplantation unit in the world would be able to perform gene correction on autografts independently.
The development of an industrial process would be a further step toward the generalization of gene therapy for the many patients with hereditary diseases of the hematopoietic system. It would also pave the way to gene therapy for diseases outside the hematopoietic system. The authors thank the patients' families for their continuous support of the study; the medical and nursing staff of the Immunology and Pediatric Hematology Department, Necker's Hospital, for patient care; and the staff of the Biotherapy Department, Necker's Hospital, for their work and support.
National Center for Biotechnology Information , U. Human Gene Therapy. Hum Gene Ther. Published online Jan Find articles by Salima Hacein-Bey-Abina. Author information Article notes Copyright and License information Disclaimer. E-mail: Email: m. E-mail: Email: salima. Received Oct 7; Accepted Jan Copyright , Mary Ann Liebert, Inc. This article has been cited by other articles in PMC.
Abstract More than 20 years ago, X-linked severe combined immunodeficiency SCID-X1 appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy. Introduction G ene therapy has proven to be a powerful strategy for the complementation of several monogenic, inherited diseases of the hematopoietic system. There were several reasons behind this choice: 1. Clinical Results Table 1 summarizes the results of the various clinical trials.
Table 1. Summary of X-Linked severe combined immunodeficiency gene therapy trials. Open in a separate window. Toward a Comprehensive Integrome Analysis and Greater Safety The development of leukemic SAEs after gene therapy has deeply challenged our understanding of gammaretroviral vector integration and has revealed the acute need for animal models that can predict the genotoxicity of integrating viral vectors.
Some Biological and Clinical Comments, and Expected Improvements Self-inactivating vectors have formally demonstrated their improved safety profile relative to LTR-driven retroviral vectors , as no SAEs have been observed since their first use in clinical trials in Author Disclosure There are no conflicts of interest.
References 1. Cell ; 73 — [ PubMed ] [ Google Scholar ]. Leonard WJ. The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling.
B cell-intrinsic signaling through IL receptor and STAT3 is required for establishing long-lived antibody responses in humans. Buckley RH. Primary immunodeficiency diseases: dissectors of the immune system. Lancet ; — [ PubMed ] [ Google Scholar ]. Cavazzana-Calvo M, and Gisselbrecht S. Mulligan RC. Development of gene transfer technology. Blood ; 89 — [ PubMed ] [ Google Scholar ]. Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells.
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