AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse.
AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse.
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作者：
完全性尿素酶I缺乏是最不严重的尿素循环障碍，其特征为高胆固醇血症和罕见的高氨血症发作。患者患有神经功能缺损，伴有皮质和锥体束退化、痉挛、肌萎缩和癫痫发作，并伴有智力残疾。在小鼠中，从第15天左右开始，体重减轻预示着发病;步态不稳定，随后进展为无法站立，并出现尾部震颤伴震颤样活动和死亡。在这里，我们报告了高胆固醇血症小鼠脑内用腺相关病毒表达的胆固醇酶治疗，并长期缺乏任何与脑功能障碍一致的表现。行为和组织病理学评价表明，给药小鼠与同窝小鼠无法区分，并且与神经毒性相关的推定化合物减少。此外，治疗导致生命早期代谢异常几乎完全消退;然而，随着转基因表达的下降，后期出现一些紊乱。铵激发显示，处理的小鼠受到的外源性负荷的影响远大于同窝出生的小鼠。这些结果表明，基于AAV的高丙氨酸血症疗法是有效的，并防止高丙氨酸血症小鼠模型中神经异常和认知功能障碍的发展;然而，氮挑战揭示了这些小鼠在处理废氮方面仍然受损。
Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation, and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.
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影响因子：
5.3
作者：
Iyer, RK;Yoo, PK;Cederbaum, SD
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Cederbaum, SD
影响因子：
3.6
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Hogg, S
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Marescau, B;Nagels, G;DeDeyn, PP
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影响因子：
4.2
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Iyer, R;Jenkinson, CP;Cederbaum, S
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Cederbaum, S
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5.1
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Picker, JD;Puga, AC;Cox, GF
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