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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ERetroviral vectors are widely used in gene therapy for a variety of monogenic disorders, although several studies have noted an increase in adverse events. The ability to analyze vector integration sites is important for safety monitoring. This study provides information on molecular tracking of individual hematopoietic clones in humans.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Emolecular tracking\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ehematopoietic clones\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ehumans\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eretroviral vector insertional barcoding\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003ELuca Biasco, PhD, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy, presented the results of the first molecular tracking of individual hematopoietic clones in humans [Biasco L et al. \u003Cem\u003EBlood.\u003C\/em\u003E 2014]. Data from these studies demonstrated that retroviral vector insertional barcoding will likely be an essential element in the design of therapeutic approaches for hematological disorders and cancers.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EThe use of viral vectors for gene therapy (GT) in which the patient\u2019s own hematopoietic stem cells (HSCs) are harvested, exposed in the laboratory to a viral vector carrying the corrected gene sequences, and then re-infused into the patient, may provide curative therapy for several monogenic diseases [Kaufmann KB et al. \u003Cem\u003EEMBO Mol Med.\u003C\/em\u003E 2013].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EProf Biasco reported the results of a phase 1\/2 clinical trial [Aiuti A et al. \u003Cem\u003EScience.\u003C\/em\u003E 2013] in which 3 patients with Wiskott-Aldrich syndrome (WAS) were treated with gene-corrected HSCs after pretreatment with a reduced-intensity myeloablative regimen. Administration of autologous HSCs transduced with lentiviral vectors at \u0026gt;\u200990% was associated with the following: robust gene transfer in unfused CD34+cells; persistent multilineage engraftment; restoration of WAS expression to near-physiological levels; immunologic and hematologic improvement; and clinical benefit. Clonal tracking of stem-cell dynamics by vector insertions showed details of hematopoietic reconstitution after GT. Seven patients have been treated so far using this protocol with similar positive results and no severe adverse events or evidence of leukemia.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EAnother study has found that GT, combined with reduced-intensity conditioning, is safe and effective in the treatment of severe combined immunodeficiency due to the lack of adenosine deaminase [Aiuti A et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E. 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003ELinear amplification-mediated polymerase chain reaction is a powerful tool for analyzing integration sites and enriching for specific vector gene function. When combined with Illumina-Miseq sequencing, it becomes a tool to identify the clonal engraftment of the cells that have been barcoded and re-infused into the patient. To date, Prof Biasco\u2019s group has used this technology to record the clonal diversity of gene-corrected cells from \u0026gt;\u200989\u2009000 clones and to mark the recapture of identical clones over time. These clones belong to 13 different cell types purified from the bone marrow and the peripheral blood of 4 patients with WAS up to 4 years after GT.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe technique also made it possible to identify 3 major waves of clonal reconstitution. Clones that were detected 9 months after GT showed the highest relationship and were stable over time. This protocol has also helped to identify the detection of multipotent progenitors, the clonal output of CD43+progenitors, and the relationship between HSPC and mature lineages.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EProf Biasco concluded that in vitro activated hematopoietic stem and progenitor cells (HSPC) could sustain long-term hematopoiesis; multipotency could be exerted long-term with fluctuating outputs; and a few thousand HSPC clones are responsible for the maintenance of steady-state hematopoiesis. In addition, there is evidence of a defined switch between short- and long-term engrafting of HSPC, while takeover of hematopoiesis by HSPC could occur between 6 and 12 months after transplant, and clonal diversity stabilizes at 12 months after GT.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/55\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo9aq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}