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Abstract:
:Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis.
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最新影响因子:11.047 | 期刊ISSN:0390-6078 | CiteScore:4.28 |
出版周期: | 是否OA:YES | 出版年份:0 |
期刊官方网址:http://haematologica.org/
自引率:4.00% | 研究方向:HEMATOLOGY- |
出版地区:ITALY |
SCI期刊coverage:Science Citation Index Expanded(科学引文索引扩展)
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Published by Ferrata Storti Foundation. ISSN: 0390-6078.
由Ferrata Storti基金会出版。ISSN: 0390 - 6078。
大类(学科) | 小类(学科) | 学科排名 |
医学 |
HEMATOLOGY (血液学) 2区 |
5/71 |
年度总发文量 | 年度论文发表量 | 年度综述发表量 |
239 | 225 | 14 |
引文计数(2018)
文献(2015-2017)
4418次引用
1032篇文献
序号 | 类别 | 排名 | 百分位 |
1 |
大类(学科):Medicine
小类(学科):Hematology
|
#9/120
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研究方向:凝血
接受率: 比较困难(25%命中)
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研究方向:医药科学 血液系统
审稿时间: 2个月内
影响因子:2.67
ISSN:1054-6006
研究方向:农林科学-海洋学
影响因子:3.906
ISSN:1054-3139
研究方向:农林科学-海洋学
影响因子:3.994
ISSN:0304-4203
研究方向:化学-海洋学
影响因子:5.763
ISSN:0022-2828
研究方向:医学-细胞生物学
影响因子:3.128
ISSN:2228-5806
研究方向:CELL BIOLOGY-
影响因子:5.063
ISSN:2044-5040
研究方向:CELL BIOLOGY-
影响因子:0.308
ISSN:0884-6812
研究方向:CELL BIOLOGY-
影响因子:2.5
ISSN:0025-3235
研究方向:地学-地球化学与地球物理
影响因子:2.049
ISSN:0377-0265
研究方向:地学-地球化学与地球物理
发表一篇学和医学成像类SCI论文
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