Low incidence of hepatocellular carcinoma in mice and cats treated with systemic adeno-associated viral vectors.
Low incidence of hepatocellular carcinoma in mice and cats treated with systemic adeno-associated viral vectors.
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全身腺相关病毒载体治疗的小鼠和猫肝细胞癌发病率低。
DOI：
10.1016/j.omtm.2020.11.015
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发表时间：
2021-03-12
期刊：
影响因子：
--
通讯作者：
Auricchio A
中科院分区：
文献类型：
--
作者：
Ferla R;Alliegro M;Dell'Anno M;Nusco E;Cullen JM;Smith SN;Wolfsberg TG;O'Donnell P;Wang P;Nguyen AD;Chandler RJ;Chen Z;Burgess SM;Vite CH;Haskins ME;Venditti CP;Auricchio A
腺相关病毒（AAV）载体由于其组合的功效和安全性而成为用于体内基因转移的优选平台。然而，插入突变与随后的肝细胞癌（HCC）的发展已被反复注意到在新生小鼠用高剂量的AAV治疗，最近，野生型AAV整合在一个子集的人HCC的关联已被记录。在这里，我们解决，在一个全面的，前瞻性的研究，在年轻的成年小鼠的长期致瘤性的风险后，交付的单链腺相关病毒靶向肝脏。用治疗性AAV和报告基因AAV治疗的小鼠中的HCC发病率较低，与先前在用较高剂量的AAV治疗的新生小鼠中记录的相反。具体地，HCC在76只AAV处理的小鼠中的6只中发展，并且仅在一个肿瘤中发现AAV的致病性整合。此外，在载体施用后长达8年的青少年AAV治疗的粘多糖样变性VI型（MPS VI）猫中未发现肝肿瘤发生的证据。总之，我们的结果支持与AAV介导的靶向青少年/年轻成人肝脏的基因转移相关的肿瘤发生的低风险，尽管建议对入组AAV临床试验的受试者进行持续监测。全身递送高剂量的腺相关病毒（AAV）载体在新生小鼠中引起插入诱变和肝细胞癌。该研究表明，使用与许多临床应用中使用的剂量相似的AAV剂量的年轻成年小鼠和幼年猫的这种风险较低。
Adeno-associated viral (AAV) vectors have emerged as the preferred platform for in vivo gene transfer because of their combined efficacy and safety. However, insertional mutagenesis with the subsequent development of hepatocellular carcinomas (HCCs) has been recurrently noted in newborn mice treated with high doses of AAV, and more recently, the association of wild-type AAV integrations in a subset of human HCCs has been documented. Here, we address, in a comprehensive, prospective study, the long-term risk of tumorigenicity in young adult mice following delivery of single-stranded AAVs targeting liver. HCC incidence in mice treated with therapeutic and reporter AAVs was low, in contrast to what has been previously documented in mice treated as newborns with higher doses of AAV. Specifically, HCCs developed in 6 out 76 of AAV-treated mice, and a pathogenic integration of AAV was found in only one tumor. Also, no evidence of liver tumorigenesis was found in juvenile AAV-treated mucopolysaccharidosis type VI (MPS VI) cats followed as long as 8 years after vector administration. Together, our results support the low risk of tumorigenesis associated with AAV-mediated gene transfer targeting juvenile/young adult livers, although constant monitoring of subjects enrolled in AAV clinical trial is advisable. Systemic delivery of high doses of adeno-associated viral (AAV) vectors causes insertional mutagenesis and hepatocellular carcinomas in newborn mice. The study shows that this risk is lower in young adult mice and juvenile cats using AAV doses similar to those used in many clinical applications.
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影响因子：
15.9
作者：
Chandler, Randy J.;LaFave, Matthew C.;Venditti, Charles P.
通讯作者：
Venditti, Charles P.
影响因子：
4.8
作者：
Ansari, Amir Mehdi;Ahmed, A. Karim;Matsangos, Aerielle E.;Lay, Frank;Born, Louis J.;Marti, Guy;Harmon, John W.;Sun, Zhaoli
通讯作者：
Sun, Zhaoli
DOI：
10.1016/j.omtm.2017.07.004
发表时间：
2017-09-15
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Ferla R;Alliegro M;Marteau JB;Dell'Anno M;Nusco E;Pouillot S;Galimberti S;Valsecchi MG;Zuliani V;Auricchio A
通讯作者：
Auricchio A
影响因子：
12.4
作者：
Cotugno, Gabriella;Annunziata, Patrizia;Auricchio, Alberto
通讯作者：
Auricchio, Alberto
影响因子：
1.5
作者：
BLACKWELL, BN;BUCCI, TJ;TURTURRO, A
通讯作者：
TURTURRO, A