Mucopolysaccharidosis type IVA (MPS IVA) is due to the deficiency of GALNS (N-acetylgalactosamine 6-sulfate sulfatase) and is characterized by systemic skeletal dysplasia. We have evaluated adeno-associated virus 8 (AAV8) vectors expressing different forms of human GALNS under a liver-specific promoter. The vectors were delivered intravenously into 4-week-old MPS IVA knockout (KO) and immune tolerant (MTOL) mice at a dose of 5 × 10¹³ genome copies (GC)/kg. These mice were monitored for 12 weeks post-injection. GALNS enzyme activity was elevated significantly in plasma of all treated mice at 2 weeks post-injection. The activity observed was 4- to 19-fold higher than that in wild-type mice and was maintained throughout the monitoring period. Treatment with AAV vectors resulted in a reduction of keratan sulfate (KS) levels in plasma to normal levels 2 weeks post-injection, which were maintained until necropsy. Both vectors reduced the storage in articular cartilage, ligaments, and meniscus surrounding articular cartilage and growth plate region as well as heart muscle and valves. Our results suggest that the continuous presence of high levels of circulating enzyme increases the penetration into bone and heart and reduces the KS level, thereby improving storage in these regions. The current data support a strategy for developing a novel treatment to address the bone and heart disease in MPS IVA using AAV gene therapy.

IVA型粘多糖贮积症（MPS IVA）是由于GALNS（ N-乙酰半乳糖胺6-硫酸酯硫酸酯酶）缺乏所致，其特征是全身性骨骼发育不良。我们评估了在肝脏特异性启动子下表达不同形式的人类 GALNS 的腺相关病毒 8 (AAV8) 载体。将载体以5×10 ¹³基因组拷贝(GC)/kg的剂量静脉注射至4周大的MPS IVA敲除(KO)和免疫耐受(MTOL)小鼠中。注射后对这些小鼠进行 12 周的监测。注射后 2 周，所有接受治疗的小鼠血浆中的 GALNS 酶活性均显着升高。观察到的活性比野生型小鼠高 4 至 19 倍，并且在整个监测期间保持不变。 AAV 载体治疗导致注射后 2 周血浆中硫酸角质素 (KS) 水平降低至正常水平，并一直维持到尸检。两种载体都减少了关节软骨、韧带和关节软骨周围的半月板和生长板区域以及心肌和瓣膜的储存。我们的结果表明，高水平循环酶的持续存在增加了对骨骼和心脏的渗透，并降低了 KS 水平，从而改善了这些区域的储存。目前的数据支持使用 AAV 基因疗法开发一种新疗法来解决 MPS IVA 中的骨骼和心脏病的策略。