Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections
Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections
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DOI：
10.1007/s00439-019-01992-z
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发表时间：
2019-04-01
期刊：
影响因子：
5.3
通讯作者：
Reiss, Jochen
中科院分区：
文献类型：
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作者：
Reiss, Jochen
钼辅因子缺乏症是一种常染色体遗传性代谢紊乱，在缺乏有效治疗的情况下，会导致儿童早期因神经功能恶化而死亡。在A型疾病中，缺少环吡喃蝶呤单磷酸（cPMP），这是辅助因子生物合成中的第一个中间体，并且已经开发了使用cPMP的生化替代疗法。到目前为止，用于B型疾病的类似方法在合成的第二步中存在缺陷，即形成阿多巴蝶呤，该方法受到相应代谢物的极端不稳定性的阻碍。为了探索成功和安全的基因疗法的途径，建立了携带突变c.88C>T（p.Q30X）和c.726_727delAA的敲入小鼠模型，这些突变也在人类患者中发现。重组腺相关病毒（rAAV）的构建和用于出生后MoCo缺陷小鼠的肝内注射的概念验证的方法。在60只动物中单次给予适当的病毒剂量可在不同程度上防止破坏性表型。虽然未经处理的小鼠存活时间不超过20周，但一些经过处理的小鼠在两种性别中都长大成人。
Molybdenum cofactor deficiency is an autosomal, recessively inherited metabolic disorder, which, in the absence of an effective therapy, leads to early childhood death due to neurological deterioration. In type A of the disease, cyclic pyranopterin monophosphate (cPMP) is missing, the first intermediate in the biosynthesis of the cofactor, and a biochemical substitution therapy using cPMP has been developed. A comparable approach for type B of the disease with a defect in the second step of the synthesis, formation of molybdopterin, so far has been hampered by the extreme instability of the corresponding metabolites. To explore avenues for a successful and safe gene therapy, knock-in mouse models were created carrying the mutations c.88C>T (p.Q30X) and c.726_727delAA, which are also found in human patients. Recombinant adeno-associated viruses (rAAVs) were constructed and used for postnatal intrahepatic injections of MoCo-deficient mice in a proof-of-concept approach. Singular administration of an appropriate virus dose in 60 animals prevented the otherwise devastating phenotype to a variable extent. While untreated mice did not survive for more than 2weeks, some of the treated mice grew up to adulthood in both sexes.