Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB
Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB
复制标题
DOI：
10.1073/pnas.1416660111
复制
发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Neufeld, Elizabeth F.
中科院分区：
文献类型：
--
作者：
Kan, Shih-hsin;Aoyagi-Scharber, Mika;Neufeld, Elizabeth F.
粘多糖病IIIB型（MPS IIIB， Sanfilippo综合征B型）是一种溶酶体贮积性疾病，其特征是深度智力残疾、痴呆，寿命约为20年。其原因是编码α - n -乙酰氨基葡萄糖苷酶（NAGLU）基因突变、NAGLU缺乏和硫酸肝素积累。酶替代治疗的障碍是重组人NAGLU和血脑屏障上缺乏甘露糖6-磷酸。为了克服第一个障碍，我们制备了重组NAGLU和胰岛素样生长因子II （IGFII）片段的融合蛋白，供甘露糖6-磷酸/IGFII受体内吞。为了绕过血脑屏障，将人工脑脊液（“载体”）中的融合蛋白（“酶”）注入成年MPS IIIB小鼠的脑室内，在2周内给药4次。1-28 d后分析脑区，并与单独接受载药的MPS IIIB小鼠或接受载药的对照（杂合）小鼠的脑区进行比较。给药酶在大脑的许多部位有明显的吸收，其半衰期约为10天。硫酸肝素，特别是特定疾病的硫酸肝素，被降低到控制水平。神经元中的一些次级积累[β -己糖氨酸酶、LAMP1（溶酶体相关膜蛋白1）、SCMAS（线粒体ATP合成酶亚基c）、glyypican 5、β -淀粉样蛋白、P-tau]几乎降低到对照水平。CD68，一种小胶质蛋白，被还原了一半。大量的酶也出现在肝细胞中，它将硫酸肝素和β -己糖氨酸酶的积累减少到控制水平。这些结果提示酶替代治疗MPS IIIB的可行性。
Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding alpha-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood-brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [beta-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, beta-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and beta-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.