Longitudinal imaging of therapeutic enzyme expression after gene therapy for Fabry disease using positron emission tomography and the radiotracer [18F]AGAL.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Charalambos Kaittanis, Tyler Teceno, Ashley Knight, Yoann Petibon, Phil Sandoval, Lawrence Cohen, Shin Hye Ahn, Anthony P Belanger, Louise M Clark, Quang-De Nguyen, Wanida Ruangsiriluk, Shreya Mukherji, Cristian C Constantinescu, Amy Llopis Amenta, Sarav Narayanan, Mugdha Deshpande, Rizwana Islam, Shipeng Yuan, Paul McQuade, Christopher T Winkelmann, Talakad G Lohith
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Abstract

Longitudinal, non-invasive, in vivo monitoring of therapeutic gene expression is an unmet need for gene therapy (GT). Positron emission tomography (PET) radiotracers designed to bind to therapeutic proteins may provide a sensitive imaging platform to guide treatment response and dose optimization in GT. Herein, we evaluate a novel PET tracer ([18F]AGAL) for targeting α-galactosidase A (GLA), an enzyme deficient in Fabry disease. Gla knockout mice were subjected to either GT with an adeno-associated virus encoding the human GLA (AAVGLA) or recombinant GLA for enzyme replacement studies. PET imaging, ex vivo autoradiography, biochemical analyses and radiation dosimetry were performed. [18F]AGAL exhibited pH-dependent binding to GLA, suggesting recognition of the active enzyme residing within the acidified lysosomes. Imaging studies in the Fabry mouse model showed quick renal clearance with high radioactive uptake in the heart at 6 weeks that was sustained for 26 weeks after a single administration of AAVGLA, indicating effective and durable transgene expression from GT. Good concordance was achieved between in vivo PET imaging and ex vivo quantification of GLA levels in biofluids and tissues. Biodistribution and dosimetry in non-human primate showed acceptable radiation exposure for multiple injections, demonstrating its potential for translation to clinical trial use.

利用正电子发射断层扫描和放射性示踪剂 [18F]AGAL 对法布里病基因治疗后的治疗酶表达进行纵向成像。
对治疗基因表达进行纵向、无创、体内监测是基因治疗(GT)尚未满足的需求。与治疗蛋白结合的正电子发射断层扫描(PET)放射性示踪剂可提供一个灵敏的成像平台,指导基因治疗中的治疗反应和剂量优化。在此,我们评估了一种新型 PET 示踪剂([18F]AGAL),用于靶向法布里病中缺乏的一种酶--α-半乳糖苷酶 A(α-GalA)。用编码人 a-Gal A 的腺相关病毒(AAVGLA)或重组 α-GalA 对 Gla 基因敲除小鼠进行 GT,以进行酶替代研究。研究人员进行了 PET 成像、体内外自显影、生化分析和辐射剂量测定。[18F]AGAL表现出与a-GalA的pH依赖性结合,表明它能识别酸化溶酶体中的活性酶。在法布里小鼠模型中进行的成像研究显示,单次给药 AAVGLA 后,小鼠的肾脏很快清除了 AAVGLA,但心脏在 6 周时仍有较高的放射性摄取,并持续了 26 周,这表明 GT 转基因表达有效且持久。体内 PET 成像与生物流体和组织中 α-GalA 水平的体外定量分析之间实现了良好的一致性。在非人灵长类动物体内进行的生物分布和剂量测定显示,多次注射的辐射暴露量是可接受的,这表明它有潜力应用于临床试验。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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