在野生型和法布里病小鼠模型中,将抗体-药物共轭物作为造血干细胞靶向基因疗法的前提条件的实用性

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Molecular genetics and metabolism Pub Date : 2024-05-15 DOI:10.1016/j.ymgme.2024.108494
Jin Ogata , Yohta Shimada , Toya Ohashi , Hiroshi Kobayashi
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引用次数: 0

摘要

背景法布里病(FD)的特征是α-半乳糖苷酶 A(GLA)活性不足。因此,球藻糖基甘油三酯(Gb3)会在多个器官中积累,造成心脏、肾脏和脑血管损伤。针对 FD 的基因疗法已在人体中进行了研究。造血干细胞靶向基因疗法(HSC-GT)需要强调理。然而,强调理会导致各种副作用,应避免使用。在这项研究中,我们测试了在野生型和法布里模型小鼠中进行基于抗体的造血干细胞靶向基因治疗的调理方法。在野生型实验中,将 EGFP 基因导入造血干细胞并移植到预处理小鼠体内,分析供体嵌合度和 EGFP 表达。在法布里小鼠模型中,将 GLA 基因导入造血干细胞并移植到预处理的法布里小鼠体内。结果在野生型小鼠实验中,当使用抗-CD45抗体-药物共轭物时,6个月时供体细胞的比例为64.5%,69.6%的移植供体外周血表达了EGFP。当使用抗 CD117 抗体-药物共轭物和 ATG 时,6 个月后供体细胞的比例为 80.7%,73.4% 的移植供体外周血表达了 EGFP。结论基于抗体的预处理可能是治疗 FD 的 HSC-GT 的另一种预处理策略。
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Usefulness of antibody-drug conjugate as preconditioning for hematopoietic stem cell-targeted gene therapy in wild-type and Fabry disease mouse models

Background

Fabry disease (FD) is characterized by deficient activity of α-galactosidase A (GLA). Consequently, globotriaosylceramide (Gb3) accumulates in various organs, causing cardiac, renal, and cerebrovascular damage. Gene therapies for FD have been investigated in humans. Strong conditioning is required for hematopoietic stem cell-targeted gene therapy (HSC-GT). However, strong conditioning leads to various side effects and should be avoided. In this study, we tested antibody-based conditioning for HSC-GT in wild-type and FD model mice.

Methods

After preconditioning with an antibody-drug conjugate, HSC-GT using a lentiviral vector was performed in wild-type and Fabry model mice. In the wild-type experiment, the EGFP gene was introduced into HSCs and transplanted into preconditioned mice, and donor chimerism and EGFP expression were analyzed. In the FD mouse model, the GLA gene was introduced into HSCs and transplanted into preconditioned Fabry mice. GLA activity and Gb3 accumulation in the organs were analyzed.

Results

In the wild-type mouse experiment, when anti-CD45 antibody-drug conjugate was used, the percentage of donor cells at 6 months was 64.5%, and 69.6% of engrafted donor peripheral blood expressed EGFP. When anti-CD117 antibody-drug conjugate and ATG were used, the percentage of donor cells at 6 months was 80.7%, and 73.4% of engrafted donor peripheral blood expressed EGFP. Although large variations in GLA activity among mice were observed in the FD mouse experiment for both preconditioning regimens, Gb3 was significantly reduced in many organs.

Conclusions

Antibody-based preconditioning may be an alternative preconditioning strategy for HSC-GT for treating FD.

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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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