PDF(Pubmed)
Abstract：
Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.
摘要：
II型粘多糖贮积症（MPSII）是由艾杜糖醛酸-2-硫酸酯酶（IDS）缺乏引起的X连锁隐性溶酶体疾病，导致糖胺聚糖（GAG）的积累和进行性疾病的出现。酶替代疗法是目前唯一被批准的治疗方法,但它使神经系统疾病得不到解决。脑脊液(CSF)定向施用AAV9。CB7.HIDS(RGX-121)是一种替代治疗策略，但尚不清楚这种方法是否会影响神经系统和全身表现。我们比较了在MPSII小鼠模型中以一定范围的载体剂量鞘内（i.t.）和静脉内（i.v.）给药途径（ROA）的有效性。虽然低剂量完全无效，1×109gc的总剂量可在血浆中而不是组织中产生可观的IDS活性水平。两种ROA的总剂量为1×1010和1×1011gc导致超生理血浆IDS活性，几乎所有组织中的IDS活性水平和GAG降低，和归一化的骨弓直径。在大脑中,1×1011gci.t.的剂量达到了最高的IDS活性水平和GAG含量的最大降低，它可以预防神经认知缺陷。我们得出的结论是，1×1010gc的剂量可以使代谢和骨骼结局正常化，虽然神经系统的改善需要1×1011gc的剂量，从而表明人类有类似的直接利益的前景。
