Analyzing the number of common integration sites of viral vectors--new methods and computer programs.
Analyzing the number of common integration sites of viral vectors--new methods and computer programs.
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DOI：
10.1371/journal.pone.0024247
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Schmidt M
中科院分区：
文献类型：
--
作者：
Abel U;Deichmann A;Nowrouzi A;Gabriel R;Bartholomae CC;Glimm H;von Kalle C;Schmidt M
基于γ-逆转录病毒或慢病毒的载体已被证明能稳定表达治疗性转基因，并能有效治疗各种血液病。对患者和临床前动物模型中基因校正细胞插入库的分子随访显示，宿主基因组中存在不同的整合偏好，包括小基因组区域的整合簇（CIS；常见整合位点）。在大多数情况下，这些CIS在基因中或基因附近发现，有可能影响受影响细胞的克隆命运。为了确定观察到的聚类程度是否在统计上与假设的整合体空间分布的标准模型相一致，我们开发了各种γ-逆转录病毒和慢病毒整合位点分布的方法和计算机程序。特别是，我们设计并实施了数学和统计方法，用于比较具有不同数量的整合位点的两个实验样本在形成CIS的倾向方面，以及分析从不同血室获得的整合位点的巧合。这里描述的程序和统计工具在R代码中作为工作区可用，并允许从任何逆转录病毒转导样本中快速检测过度聚集的整合位点，从而有助于评估临床前和临床逆转录病毒基因治疗研究中潜在的治疗相关风险。
Vectors based on γ-retroviruses or lentiviruses have been shown to stably express therapeutical transgenes and effectively cure different hematological diseases. Molecular follow up of the insertional repertoire of gene corrected cells in patients and preclinical animal models revealed different integration preferences in the host genome including clusters of integrations in small genomic areas (CIS; common integrations sites). In the majority, these CIS were found in or near genes, with the potential to influence the clonal fate of the affected cell. To determine whether the observed degree of clustering is statistically compatible with an assumed standard model of spatial distribution of integrants, we have developed various methods and computer programs for γ-retroviral and lentiviral integration site distribution. In particular, we have devised and implemented mathematical and statistical approaches for comparing two experimental samples with different numbers of integration sites with respect to the propensity to form CIS as well as for the analysis of coincidences of integration sites obtained from different blood compartments. The programs and statistical tools described here are available as workspaces in R code and allow the fast detection of excessive clustering of integration sites from any retrovirally transduced sample and thus contribute to the assessment of potential treatment-related risks in preclinical and clinical retroviral gene therapy studies.
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影响因子：
20.3
作者：
Du, Y;Jenkins, NA;Copeland, NG
通讯作者：
Copeland, NG
影响因子：
56.9
作者：
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影响因子：
20.3
作者：
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20.3
作者：
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Hematti P;Hong BK;Ferguson C;Adler R;Hanawa H;Sellers S;Holt IE;Eckfeldt CE;Sharma Y;Schmidt M;von Kalle C;Persons DA;Billings EM;Verfaillie CM;Nienhuis AW;Wolfsberg TG;Dunbar CE;Calmels B
通讯作者：
Calmels B