Keshavan Nandaki, Greenwood Miriam, Prunty Helen, Diaz Juan Antinao, Privolizzi Riccardo, Counsell John, Karlsson Anna, Sebire Neil, Waddington Simon, Karda Rajvinder, Rahman Shamima
UCL GOS Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Department of Metabolic Medicine, Great Ormond Street Hospital NHS Trust, Guilford St, London WC1N 3BH, UK.
Mol Ther Methods Clin Dev. 2024 Dec 13;33(1):101397. doi: 10.1016/j.omtm.2024.101397. eCollection 2025 Mar 13.
Primary mitochondrial disorders are a cause of neonatal liver failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localizing enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome, leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9- intravenously to newborn knock-out mice and showed that liver dysfunction was prevented in a dose-dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were observed. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III, and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.
原发性线粒体疾病是新生儿肝衰竭的一个病因。编码线粒体定位酶脱氧鸟苷激酶（DGUOK）的基因双等位基因致病性变异会导致肝脑线粒体DNA耗竭综合征，进而引发急性新生儿肝衰竭和早期死亡。目前尚无有效的疾病改善疗法。在本研究中，我们开发了一种腺相关病毒9（AAV9）基因治疗方法来治疗模拟人类疾病的DGUOK缺陷小鼠模型。我们将AAV9静脉注射给新生的基因敲除小鼠，结果显示肝功能障碍得到了剂量依赖性的预防。出乎新生儿给药意料的是，观察到了持久且长期的肝脏转导和RNA表达。肝脏线粒体DNA耗竭、氧化磷酸化复合体I、III和IV的缺陷以及肝转氨酶升高和生存率均得到了剂量依赖性的改善。
