PDF(Pubmed)
Abstract：
Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa, and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete (IDS.ApoE2co) or no (IDSco and IDS.RAP12x2co) correction. In contrast, tracheal, epiphyseal, and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.
摘要：
艾杜糖醛酸2-硫酸酯酶（IDS）的缺乏导致II型粘多糖贮积症（MPSII），溶酶体贮积症，以糖胺聚糖（GAG）的系统性积累为特征，导致毁灭性的认知能力下降和危及生命的呼吸和心脏并发症。我们以前发现造血干细胞和祖细胞介导的慢病毒基因疗法（HSPC-LVGT）采用标记的IDS与胰岛素样生长因子2（IGF2）或ApoE2，但不是受体相关蛋白最小肽（RAP12x2），在MPSII的小鼠模型中有效地预防了脑病理学。在这项研究中,我们报道了HSPC-LVGT对外周病理学的影响,并分析了IDS的生物分布.我们发现HSPC-LVGT与所有载体完全纠正GAG积累和溶酶体病理在肝脏，脾,脾肾,气管粘膜，和心脏瓣膜。只有使用IDS才能完全校正大心脏血管的膜介质。IGF2co基因治疗,而其他向量几乎完全提供(IDS。ApoE2co)或没有(IDSco和IDS。RAP12x2co）校正。相比之下,气管,骨phy，所有测试的载体仍未纠正关节软骨。这些功效与HSPC-LVGT后的IDS蛋白水平紧密匹配。我们的研究结果证明了HSPC-LVGT在高临床相关性组织中纠正病理的能力，包括心脏和呼吸系统，而软骨病理学的矫正仍然存在挑战。
