Combined intraocular and intravenous gene delivery for therapy of gyrate atrophy of the choroid and retina.

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-07-02 Epub Date: 2024-10-28 DOI:10.1016/j.ymthe.2024.10.019

Fabio Dell'Aquila, Roberto Di Cunto, Elena Marrocco, Eugenio Del Prete, Alfonso D'Alessio, Lucia De Stefano, Simone Notaro, Edoardo Nusco, Alberto Auricchio

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引用次数: 0

Abstract

Gyrate atrophy of the choroid and retina (GACR) is due to ornithine aminotransferase (OAT) deficiency, which causes hyperornithinemia, leading to retinal pigment epithelium, followed by choroidal and retinal degeneration. Adeno-associated virus serotype 8 (AAV8) vector-mediated OAT (AAV8-OAT) liver gene transfer reduces ornithinemia in the Oat^-/- mouse model of GACR and improves retinal function and structure. Since OAT is expressed in various tissues including the retina, we investigated the efficacy of restoration of OAT expression in either retina or liver or both tissues on the retinal phenotype of Oat^-/- mice. Intravenous and subretinal administration of AAV8-OAT resulted in intraocular and liver OAT expression with reduced ornithinemia after intravenous AAV8-OAT administration, while intraocular ornithine levels were significantly reduced only following combined gene delivery. Accordingly, only Oat^-/- animals treated with combined intravenous and subretinal AAV8-OAT administrations showed significant improvements in both retinal morphology and function. This work shows the benefits of combined liver and retinal OAT supplementation for the treatment of GACR.

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联合眼内和静脉注射基因，治疗脉络膜和视网膜回缩性萎缩。

脉络膜和视网膜回旋萎缩（GACR）是由于鸟氨酸氨基转移酶（OAT）缺乏引起高鸟氨酸血症，导致视网膜色素上皮继而脉络膜和视网膜变性。腺相关病毒血清型8（AAV8）载体介导的OAT（AAV8-OAT）肝脏基因转移可减少OAT-/-小鼠GACR模型中的鸟氨酸氨基转移酶缺乏症，并改善视网膜功能和结构。由于 OAT 在包括视网膜在内的多种组织中表达，我们研究了恢复 OAT 在视网膜、肝脏或两种组织中的表达对 Oat-/- 小鼠视网膜表型的影响。静脉注射 AAV8-OAT 和视网膜下注射 AAV8-OAT 会导致眼内和肝脏中 OAT 的表达，静脉注射 AAV8-OAT 会减少鸟氨酸血症，而只有联合基因递送才会显著降低眼内鸟氨酸水平。因此，只有联合静脉注射和视网膜下注射 AAV8-OAT 的 Oat-/- 动物的视网膜形态和功能才有明显改善。这项工作显示了联合补充肝脏和视网膜 OAT 对治疗 GACR 的益处。

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来源期刊

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.