Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice.
Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice.
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DOI：
10.1016/j.omtm.2017.05.009
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发表时间：
2017-09-15
期刊：
影响因子：
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通讯作者：
Bunting S
中科院分区：
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作者：
Aoyagi-Scharber M;Crippen-Harmon D;Lawrence R;Vincelette J;Yogalingam G;Prill H;Yip BK;Baridon B;Vitelli C;Lee A;Gorostiza O;Adintori EG;Minto WC;Van Vleet JL;Yates B;Rigney S;Christianson TM;Tiger PMN;Lo MJ;Holtzinger J;Fitzpatrick PA;LeBowitz JH;Bullens S;Crawford BE;Bunting S
桑菲里波综合征B型(粘多糖症IIIB)是一种儿童神经退行性疾病，由α-N-乙酰氨基葡萄糖苷酶(NAGLU)遗传缺陷引起，是硫酸肝素(HS)溶酶体降解所必需的，目前尚无治疗方法。脑室(Icv)注射改良的重组NAGLU，由人NAGLU与胰岛素样生长因子2(IGF2)融合而成，用于增强溶酶体靶向，先前被证明在Naglu−/−小鼠大脑中导致显著的酶摄取和HS储存的清除。为了进一步评估NAGLU-IGF2(BMN250)的区域性、细胞类型特异性和剂量依赖性的生物分布及其对生化和组织病理学的影响，Naglu−/−小鼠接受了1-100gμg icv剂量的治疗(2周内4次)。在最后一次给药后的第一天，BMN250(100gμg剂量)导致NAGLU活性水平高于正常水平，在所有类型的细胞中广泛的生物分布和摄取，NAGLU主要定位于Naglu−/−小鼠脑内的神经元。这导致了疾病特异性HS的完全清除，并减少了继发性溶酶体缺陷和大脑不同区域的神经病理，持续了至少28天。这一最高icv剂量所能达到的脑组织对NAGLU的大量摄取是几乎完全减弱疾病驱动的储存积累和整个Naglu−/−小鼠大脑的神经病理所必需的。
Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu−/− mouse brain. To further evaluate regional, cell type-specific, and dose-dependent biodistribution of NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu−/− mice were treated with 1–100 μg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 μg doses) resulted in above-normal NAGLU activity levels, broad biodistribution, and uptake in all cell types, with NAGLU predominantly localized to neurons in the Naglu−/− mouse brain. This led to complete clearance of disease-specific HS and reduction of secondary lysosomal defects and neuropathology across various brain regions lasting for at least 28 days after the last dose. The substantial brain uptake of NAGLU attainable by this highest ICV dosage was required for nearly complete attenuation of disease-driven storage accumulations and neuropathology throughout the Naglu−/− mouse brain.