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首页> 外文期刊>The European Journal of Neuroscience >Examination of intravenous and intra-CSF protein delivery for treatment of neurological disease.
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Examination of intravenous and intra-CSF protein delivery for treatment of neurological disease.

机译：检查静脉和脑脊液内蛋白的递送，以治疗神经系统疾病。

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Mucopolysaccharidosis type IIIA is a neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Absent or greatly reduced activity of sulphamidase, a lysosomal protein, results in intracellular accumulation of heparan sulphate. Subsequent neuroinflammation and neurodegeneration typify this and many other lysosomal storage disorders. We propose that intra-cerebrospinal fluid protein delivery represents a potential therapeutic avenue for treatment of this and other neurodegenerative conditions; however, technical restraints restrict examination of its use prior to adulthood in mice. We have used a naturally-occurring Mucopolysaccharidosis type IIIA mouse model to determine the effectiveness of combining intravenous protein replacement (1 mg/kg) from birth to 6 weeks of age with intra-cerebrospinal fluid sulphamidase delivery (100 microg, fortnightly from 6 weeks) on behaviour, the level of heparan sulphate-oligosaccharide storage and other neuropathology. Mice receiving combination treatment exhibited similar clinical improvement and reduction in heparan sulphate storage to those only receiving intra-cerebrospinal fluid enzyme. Reductions in micro- and astrogliosis and delayed development of ubiquitin-positive lesions were seen in both groups. A third group of intravenous-only treated mice did not exhibit clinical or neuropathological improvements. Intra-cerebrospinal fluid injection of sulphamidase effectively, but dose-dependently, treats neurological pathology in Mucopolysaccharidosis type IIIA, even when treatment begins in mice with established disease.
机译：IIIA型粘多糖贮积病是一种神经退行性溶酶体贮积病，其特征是学习技能逐渐丧失，睡眠障碍和行为问题。溶酶体蛋白磺酰胺酶的活性缺乏或大大降低，会导致硫酸乙酰肝素在细胞内积累。随后的神经发炎和神经退行性变是该病和许多其他溶酶体贮积病的典型代表。我们认为脑脊液内蛋白传递代表了治疗这种和其他神经退行性疾病的潜在治疗途径。但是，技术限制限制了成年小鼠在使用前的检查。我们使用了自然发生的IIIA型粘多糖贮积症小鼠模型来确定从出生到6周龄的静脉内蛋白质替代（1 mg / kg）与脑脊液内磺酰胺酶递送（100 microg，从6周起每两周一次）相结合的有效性在行为，硫酸乙酰肝素-低聚糖储存水平和其他神经病理学上。与仅接受脑脊髓液酶治疗的小鼠相比，接受联合治疗的小鼠表现出相似的临床改善和硫酸乙酰肝素存储量的减少。两组均观察到微和星形胶质细胞减少症的减少以及泛素阳性病变的延迟发展。第三组仅静脉内治疗的小鼠未表现出临床或神经病理学改善。脑脊液内注射磺酰胺酶可有效但剂量依赖性地治疗IIIA型黏多糖贮积病的神经病理学，即使在已患疾病的小鼠中开始治疗时也是如此。

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