Long-term Amelioration of Feline Mucopolysaccharidosis VI After AAV-mediated Liver Gene Transfer
Long-term Amelioration of Feline Mucopolysaccharidosis VI After AAV-mediated Liver Gene Transfer
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DOI：
10.1038/mt.2010.257
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发表时间：
2011-03-01
影响因子：
12.4
通讯作者：
Auricchio, Alberto
中科院分区：
文献类型：
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作者：
Cotugno, Gabriella;Annunziata, Patrizia;Auricchio, Alberto
粘多糖样沉积症VI（MPS VI）是由芳基硫酸酯酶B（ARSB）活性缺陷引起的，导致糖胺聚糖（GAG）的溶酶体储存。MPS VI的特征为多发性骨发育不全、器官肿大、角膜混浊和心脏瓣膜增厚。基因转移到工厂器官如肝脏可能会提供一个终身来源的分泌ARSB。我们发现，在MPS VI猫中血管内给予腺相关病毒载体（AAV）2/8-TBG-felineARSB导致ARSB表达长达1年，即研究的最后一个时间点。在新生猫中，在递送高载体剂量（6 x 10（13）基因组拷贝（gc）/kg）后实现了正常的循环ARSB活性，而在幼龄MPS VI猫中，递送低至2 x 10（12）gc/kg的AAV 2/8载体剂量导致高于正常血清ARSB水平。在显示高血清ARSB水平的MPS VI猫中（与给药时的年龄无关），我们观察到：（i）GAG蓄积清除，（ii）长骨长度改善，（iii）心脏瓣膜厚度降低，和（iv）自发活动改善。因此，AAV 2/8介导的肝脏基因转移代表了MPS VI患者的有希望的治疗策略。
Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adenoassociated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 x 10(13) genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 x 10(12) gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.