PDF(Pubmed)
Abstract：
Mucopolysaccharidosis type II (OMIM 309900) is a lysosomal storage disorder caused by iduronate 2-sulfatase (IDS) deficiency and accumulation of glycosaminoglycans, leading to progressive neurodegeneration. As intravenously infused enzyme replacement therapy cannot cross the blood-brain barrier (BBB), it fails to treat brain pathology, highlighting the unmet medical need to develop alternative therapies. Here, we test modified versions of hematopoietic stem and progenitor cell (HSPC)-mediated lentiviral gene therapy (LVGT) using IDS tagging in combination with the ubiquitous MND promoter to optimize efficacy in brain and to investigate its mechanism of action. We find that IDS tagging with IGF2 or ApoE2, but not RAP12x2, improves correction of brain heparan sulfate and neuroinflammation at clinically relevant vector copy numbers. HSPC-derived cells engrafted in brain show efficiencies highest in perivascular areas, lower in choroid plexus and meninges, and lowest in parenchyma. Importantly, the efficacy of correction was independent of the number of brain-engrafted cells. These results indicate that tagged versions of IDS can outperform untagged IDS in HSPC-LVGT for the correction of brain pathology in MPS II, and they imply both cell-mediated and tag-mediated correction mechanisms, including passage across the BBB and increased uptake, highlighting their potential for clinical translation.
摘要：
II型粘多糖贮积症（OMIM309900）是由艾杜糖醛酸2-硫酸酯酶（IDS）缺乏和糖胺聚糖积累引起的溶酶体贮积症，导致进行性神经变性.由于静脉输注酶替代疗法不能穿过血脑屏障（BBB），它不能治疗脑部病理，强调开发替代疗法的未满足的医疗需求。这里,我们使用IDS标记与普遍存在的MND启动子组合测试造血干细胞和祖细胞（HSPC）介导的慢病毒基因疗法（LVGT）的改良版本，以优化脑中的功效并研究其作用机制。我们发现用IGF2或ApoE2而不是RAP12x2标记的IDS可改善临床相关载体拷贝数的脑硫酸乙酰肝素和神经炎症的校正。在脑中移植的HSPC来源的细胞在血管周围区域显示出最高的效率，较低的脉络丛和脑膜，薄壁组织最低。重要的是,校正的疗效与脑移植细胞的数量无关.这些结果表明，IDS的标记版本可以优于HSPC-LVGT中未标记的IDS，以纠正MPSII中的脑部病理，它们暗示了细胞介导和标签介导的矫正机制，包括通过血脑屏障和增加摄取，强调他们的临床翻译潜力。
