Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies.
Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies.
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DOI：
10.1093/brain/awab123
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发表时间：
2021-09-04
期刊：
影响因子：
--
通讯作者：
Kurian MA
中科院分区：
文献类型：
--
作者：
Rossignoli G;Krämer K;Lugarà E;Alrashidi H;Pope S;De La Fuente Barrigon C;Barwick K;Bisello G;Ng J;Counsell J;Lignani G;Heales SJR;Bertoldi M;Barral S;Kurian MA
芳香族L氨基酸脱羧酶缺乏症是一种复杂的遗传性单胺合成障碍，导致多巴胺和5-羟色胺缺乏症。大多数受影响的人都有多种多样的、但往往是严重的认知和运动延迟，并有复杂的运动障碍和过早死亡的高风险。对于大多数人来说，标准的药物治疗只能提供有限的临床益处。前景看好的基因治疗方法正在涌现，尽管并不是所有患者都适合或容易获得。为了描述潜在的疾病病理生理学特征并指导精确的治疗，我们从诱导的多能干细胞中产生了一个患者来源的AADC缺乏症患者的中脑多巴胺能神经元模型。神经元模型概括了关键的疾病特征，包括AADC酶活性缺失和多巴胺代谢失调。我们观察到发育缺陷会影响突触成熟和神经元的电特性，而慢病毒基因治疗可以改善这些缺陷。重组AADC的生物信息学和生化分析预测，一个突变体的活性可以通过给予L-3，4-二羟基苯丙氨酸(L-多巴)来提高；这一假设在患者来源的神经元模型中得到证实，L-多巴处理导致多巴胺代谢产物的改善。我们的研究表明，患者衍生疾病模型提供了对AADC缺乏的神经发育后遗症的进一步洞察，以及一个强大的平台来研究和开发个性化的治疗方法。Rossignoli等人。建立首个AADC缺乏症的人源化神经元模型。他们使用这种患者衍生的神经系统来阐明疾病机制，特别是更好地定义神经发育特征，以及测试精确的治疗方法。
Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches. Rossignoli et al. develop the first humanized neuronal model of AADC deficiency. They use this patient-derived neuronal system to elucidate disease mechanisms, and in particular to better define neurodevelopmental features, as well as to test precision therapy approaches.
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DOI：
10.1038/nsb1101-963
发表时间：
2001-11-01
期刊：
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影响因子：
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作者：
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发表时间：
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期刊：
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DOI：
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发表时间：
2014-01-01
期刊：
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影响因子：
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