TAK-754的临床前开发,一种高性能的基于aav8表达凝血因子VIII的载体。

IF 4.6 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Molecular Therapy-Methods & Clinical Development Pub Date : 2025-01-28 eCollection Date: 2025-03-13 DOI:10.1016/j.omtm.2025.101424
Johannes Lengler, Markus Weiller, Franziska Horling, Josef Mayrhofer, Maria Schuster, Falko G Falkner, Irene Gil-Farina, Matthias Klugmann, Friedrich Scheiflinger, Werner Hoellriegl, Hanspeter Rottensteiner
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引用次数: 0

摘要

本报告涉及TAK-754的临床前开发,TAK-754是一种基于aav8的人因子VIII (FVIII)载体,旨在在肝脏特异性启动子的控制下,传递一种经过优化的、cpg缺失的B结构域缺失的F8转基因,用于a型血友病的基因治疗。在FVIII基因敲除小鼠中,当剂量为1.0 × 1012 TAK-754衣壳颗粒(CP)/kg或更高时,检测到血浆FVIII活性呈剂量依赖性增加。这种增加与止血效果测定中出血量的剂量依赖性减少是一致的。TAK-754 (3.1 × 1012 CP/kg)介导免疫耐受转基因人FVIII小鼠长期稳定表达。对雄性C57BL/6J小鼠单次给药剂量为1.9 × 1012 ~ 5.0 × 1013 CP/kg的TAK-754进行毒理学和生物分布评价。TAK-754最高剂量组未出现与TAK-754相关的不良临床症状。生物分布分析显示,主要在肝脏中检测到载体DNA,在其他组织中的发生率较低。整合位点分析显示,载体整合最少,在观察期内没有观察到克隆生长或先前与肝细胞癌形成相关的基因的首选整合。这些临床前研究表明TAK-754具有良好的安全性和有效性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII.

This report concerns the preclinical development of TAK-754, an AAV8-based human factor VIII (FVIII) vector designed to deliver a codon-optimized and CpG-depleted B domain-deleted F8 transgene under the control of a liver-specific promoter for gene therapy in patients with hemophilia A. A dose-dependent increase in plasma FVIII activity was detected in FVIII knockout mice at a dose of 1.0 × 1012 TAK-754 capsid particles (CP)/kg or higher. This increase was shown to be in accordance with a dose-dependent decrease in blood loss in a hemostatic efficacy assay. TAK-754 (3.1 × 1012 CP/kg) mediated long-term and stable FVIII expression in immunologically tolerant transgenic human FVIII mice. Toxicology and biodistribution assessments with a single administration of TAK-754 ranging between 1.9 × 1012 and 5.0 × 1013 CP/kg were conducted in male C57BL/6J mice. The highest TAK-754 dose occurred without TAK-754-related adverse clinical signs. Biodistribution profiling showed predominant detection in the liver with a low occurrence of vector DNA in other tissues. Integration site analysis revealed minimal vector integration, with no observations of clonal outgrowth or preferred integrations in genes previously implicated in hepatocellular carcinoma formation within the observation period. These preclinical studies demonstrate a good safety and efficacy profile for TAK-754.

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来源期刊
Molecular Therapy-Methods & Clinical Development
Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.90
自引率
4.30%
发文量
163
审稿时长
12 weeks
期刊介绍: The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.
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