• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

野生型和 R338L -tenase 复合物形成的差异是导致 R338L 因子 IX 检测差异的根源。

Differences in wild-type- and R338L-tenase complex formation are at the root of R338L-factor IX assay discrepancies.

机构信息

Freeline, Stevenage, Herts, United Kingdom.

Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom.

出版信息

Blood Adv. 2023 Feb 14;7(3):458-467. doi: 10.1182/bloodadvances.2022007435.

DOI:10.1182/bloodadvances.2022007435
PMID:35839077
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9979717/
Abstract

Adeno-associated virus (AAV) gene therapy has the potential to functionally cure hemophilia B by restoring factor (F)IX concentrations into the normal range. Next-generation AAV therapies express a naturally occurring gain-of-function FIX variant, FIX-Padua (R338L-FIX), that increases FIX activity (FIX:C) by approximately eightfold compared with wild-type FIX (FIX-WT). Previous studies have shown that R338L-FIX activity varies dramatically across different clinical FIX:C assays, which complicates the monitoring and management of patients. To better understand mechanisms that contribute to R338L-FIX assay discrepancies, we characterized the performance of R338L-FIX in 13 1-stage clotting assays (OSAs) and 2 chromogenic substrate assays (CSAs) in a global field study. This study produced the largest R338L-FIX assay dataset to date and confirmed that clinical FIX:C assay results vary over threefold. Both phospholipid and activating reagents play a role in OSA discrepancies. CSA generated the most divergent FIX:C results. Manipulation of FIX:C CSA kits demonstrated that specific activity gains for R338L-FIX were most profound at lower FIX:C concentrations and that these effects were enhanced during the early phases of FXa generation. Supplementing FX into CSA had the effect of dampening FIX-WT activity relative to R338L-FIX activity, suggesting that FX impairs WT tenase formation to a greater extent than R338L-FIX tenase. Our data describe the scale of R338L-FIX assay discrepancies and provide insights into the causative mechanisms that will help establish best practices for the measurement of R338L-FIX activity in patients after gene therapy.

摘要

腺相关病毒 (AAV) 基因治疗通过将因子 (F)IX 浓度恢复到正常范围，具有功能性治愈乙型血友病的潜力。下一代 AAV 疗法表达一种天然存在的功能获得性 FIX 变体，FIX-Padua（R338L-FIX），与野生型 FIX（FIX-WT）相比，FIX 活性（FIX:C）增加约 8 倍。先前的研究表明，R338L-FIX 活性在不同的临床 FIX:C 检测中差异很大，这使得患者的监测和管理变得复杂。为了更好地了解导致 R338L-FIX 检测差异的机制，我们在一项全球现场研究中，用 13 种 1 期凝血检测 (OSA) 和 2 种显色底物检测 (CSA) 对 R338L-FIX 的性能进行了表征。这项研究产生了迄今为止最大的 R338L-FIX 检测数据集，并证实了临床 FIX:C 检测结果差异超过三倍。磷脂和激活试剂在 OSA 差异中均起作用。CSA 产生的 FIX:C 结果差异最大。FIX:C CSA 试剂盒的操作表明，R338L-FIX 的特异性活性增益在较低的 FIX:C 浓度下最为显著，并且这些效应在 FXa 生成的早期阶段得到增强。向 CSA 中补充 FX 会使 FIX-WT 活性相对于 R338L-FIX 活性减弱，这表明 FX 对 WT 十因子形成的抑制作用比对 R338L-FIX 十因子形成的抑制作用更大。我们的数据描述了 R338L-FIX 检测差异的规模，并提供了有关导致机制的深入了解，这将有助于为基因治疗后患者的 R338L-FIX 活性测量建立最佳实践。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/d3039a8ca7d0/BLOODA_ADV-2022-007435-gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/c5ec015eb7ed/BLOODA_ADV-2022-007435-fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/bf52bb1e9ea6/BLOODA_ADV-2022-007435-gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/891775782b2a/BLOODA_ADV-2022-007435-gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/18f0056e0252/BLOODA_ADV-2022-007435-gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/e67ffd661220/BLOODA_ADV-2022-007435-gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/d3039a8ca7d0/BLOODA_ADV-2022-007435-gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/c5ec015eb7ed/BLOODA_ADV-2022-007435-fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/bf52bb1e9ea6/BLOODA_ADV-2022-007435-gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/891775782b2a/BLOODA_ADV-2022-007435-gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/18f0056e0252/BLOODA_ADV-2022-007435-gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/e67ffd661220/BLOODA_ADV-2022-007435-gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8474/9979717/d3039a8ca7d0/BLOODA_ADV-2022-007435-gr5.jpg

相似文献

1
Differences in wild-type- and R338L-tenase complex formation are at the root of R338L-factor IX assay discrepancies.野生型和 R338L -tenase 复合物形成的差异是导致 R338L 因子 IX 检测差异的根源。
Blood Adv. 2023 Feb 14;7(3):458-467. doi: 10.1182/bloodadvances.2022007435.
2
Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec.菲达尼科基因 Elaparvovec 治疗患者中因子 IX 变异 FIX-R338L 的现场研究和相关研究。
Thromb Haemost. 2024 Oct;124(10):912-921. doi: 10.1055/s-0044-1787734. Epub 2024 Jun 11.
3
Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity.因子 IX Padua（R338L）的过度活跃依赖于因子 VIIIa 辅因子活性。
JCI Insight. 2019 Jun 20;5(14):128683. doi: 10.1172/jci.insight.128683.
4
Gene therapy for hemophilia B using CB 2679d-GT: a novel factor IX variant with higher potency than factor IX Padua.使用 CB 2679d-GT 进行乙型血友病的基因治疗：一种新型因子 IX 变体，比因子 IX Padua 更有效。
Blood. 2021 May 27;137(21):2902-2906. doi: 10.1182/blood.2020006005.
5
The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy.用 AAV 肌肉基因疗法治疗的血友病 B 犬中 FIX Padua（R338L）的疗效和免疫原性风险。
Blood. 2012 Nov 29;120(23):4521-3. doi: 10.1182/blood-2012-06-440123. Epub 2012 Aug 23.
6
Incorporation of the factor IX Padua mutation into FIX-Triple improves clotting activity in vitro and in vivo.将因子 IX Padua 突变体纳入 FIX-Triple 可提高体外和体内的凝血活性。
Thromb Haemost. 2013 Aug;110(2):244-56. doi: 10.1160/TH13-02-0154. Epub 2013 May 16.
7
Factor IX assay discrepancies in the setting of liver gene therapy using a hyperfunctional variant factor IX-Padua.在使用超功能变异因子 IX-Padua 进行肝脏基因治疗的情况下，因子 IX 测定结果存在差异。
J Thromb Haemost. 2021 May;19(5):1212-1218. doi: 10.1111/jth.15281. Epub 2021 Mar 28.
8
Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants.凝血因子 IX Padua 和其他高比活变体的进化见解。
Blood Adv. 2021 Mar 9;5(5):1324-1332. doi: 10.1182/bloodadvances.2019000405.
9
Clinical Implications of Discrepancy between One-Stage Clotting and Chromogenic Factor IX Activity in Hemophilia B.血友病 B 中一期凝血和显色因子 IX 活性之间的差异的临床意义。
Thromb Haemost. 2024 Jan;124(1):32-39. doi: 10.1055/a-2142-0262. Epub 2023 Jul 26.
10
Characterization of recombinant factor IX fusion proteins enabling subcutaneous administration.重组凝血因子 IX 融合蛋白的特性研究，使其能够进行皮下给药。
J Thromb Haemost. 2024 Oct;22(10):2713-2723. doi: 10.1016/j.jtha.2024.07.007. Epub 2024 Jul 15.

引用本文的文献

1
Evaluation of One-Stage Assays for the Monitoring of Recombinant Human Factor IX Padua Activity After Etranacogene Dezaparvovec Gene Therapy.评估用于监测依特那考基因德扎帕罗韦基因治疗后重组人凝血因子IX帕多瓦活性的一步法检测
Haemophilia. 2025 Jul;31(4):799-806. doi: 10.1111/hae.70053. Epub 2025 Jun 18.
2
UKHCDO gene therapy taskforce: Guidance for implementation of haemophilia gene therapy into routine clinical practice for adults.英国血友病基因治疗指导小组：将血友病基因治疗应用于成人常规临床实践的实施指南。
Haemophilia. 2025 Jan;31(1):26-38. doi: 10.1111/hae.15125. Epub 2024 Nov 20.
3
Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec.

本文引用的文献

1
Factor IX assay discrepancies in the setting of liver gene therapy using a hyperfunctional variant factor IX-Padua.在使用超功能变异因子 IX-Padua 进行肝脏基因治疗的情况下，因子 IX 测定结果存在差异。
J Thromb Haemost. 2021 May;19(5):1212-1218. doi: 10.1111/jth.15281. Epub 2021 Mar 28.
2
Gene therapy for hemophilia.血友病的基因治疗。
Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):1-8. doi: 10.1182/hematology.2019000007.
3
Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B.
菲达尼科基因 Elaparvovec 治疗患者中因子 IX 变异 FIX-R338L 的现场研究和相关研究。
Thromb Haemost. 2024 Oct;124(10):912-921. doi: 10.1055/s-0044-1787734. Epub 2024 Jun 11.
4
CRISPR-Mediated In Situ Introduction or Integration of in Human iPSCs for Gene Therapy of Hemophilia B.CRISPR 介导的人诱导多能干细胞原位导入或整合用于乙型血友病的基因治疗。
Int J Mol Sci. 2023 May 19;24(10):9013. doi: 10.3390/ijms24109013.
5
Gene therapy for hemophilia: looking beyond factor expression.血友病的基因治疗：超越因子表达。
Exp Biol Med (Maywood). 2022 Dec;247(24):2223-2232. doi: 10.1177/15353702221147565. Epub 2023 Jan 23.
依特兰基因疗法（AMT-061 二期临床试验）：乙型血友病患者体内正常/接近正常的因子 IX 活性和出血停止。
Blood Adv. 2019 Nov 12;3(21):3241-3247. doi: 10.1182/bloodadvances.2019000811.
4
Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies.密码子优化对凝血因子 IX 翻译和结构的影响：对蛋白质和基因治疗的启示。
Sci Rep. 2019 Oct 29;9(1):15449. doi: 10.1038/s41598-019-51984-2.
5
The evolution of recombinant factor replacement for hemophilia.血友病重组因子替代疗法的演变
Transfus Apher Sci. 2019 Oct;58(5):596-600. doi: 10.1016/j.transci.2019.08.010. Epub 2019 Aug 9.
6
Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity.因子 IX Padua（R338L）的过度活跃依赖于因子 VIIIa 辅因子活性。
JCI Insight. 2019 Jun 20;5(14):128683. doi: 10.1172/jci.insight.128683.
7
Potential role of activated factor VIII (FVIIIa) in FVIIa/tissue factor-dependent FXa generation in initiation phase of blood coagulation.活化因子VIII（FVIIIa）在凝血起始阶段FVIIa/组织因子依赖性FXa生成中的潜在作用。
Int J Hematol. 2019 Apr;109(4):390-401. doi: 10.1007/s12185-019-02611-3. Epub 2019 Feb 13.
8
Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.用于血友病基因治疗的蛋白质工程凝血因子
Mol Ther Methods Clin Dev. 2018 Dec 31;12:184-201. doi: 10.1016/j.omtm.2018.12.007. eCollection 2019 Mar 15.
9
Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B.腺相关病毒载体 5-人凝血因子 IX 基因治疗乙型血友病成人患者。
Blood. 2018 Mar 1;131(9):1022-1031. doi: 10.1182/blood-2017-09-804419. Epub 2017 Dec 15.
10
Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.采用高特异性活性因子IX变体的B型血友病基因疗法。
N Engl J Med. 2017 Dec 7;377(23):2215-2227. doi: 10.1056/NEJMoa1708538.