PDF(Pubmed)
Abstract：
Mucopolysaccharidosis Type IIIB (MPS IIIB) is an ultrarare, fatal pediatric disease with no approved therapy. It is caused by mutations in the gene encoding for lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Tralesinidase alfa (TA) is a fusion protein comprised of recombinant NAGLU and a modified human insulin-like growth factor 2 that is being developed as an enzyme replacement therapy for MPS IIIB. Since MPS IIIB is a pediatric disease the safety/toxicity, pharmacokinetics and biodistribution of TA were evaluated in juvenile non-human primates that were administered up to 5 weekly intracerebroventricular (ICV) or single intravenous (IV) infusions of TA. TA administered by ICV slow-, ICV isovolumetric bolus- or IV-infusion was well-tolerated, and no effects were observed on clinical observations, electrocardiographic or ophthalmologic parameters, or respiratory rates. The drug-related changes observed were limited to increased cell infiltrates in the CSF and along the ICV catheter track after ICV administration. These findings were not associated with functional changes and are associated with the use of ICV catheters. The CSF PK profiles were consistent across all conditions tested and TA distributed widely in the CNS after ICV administration. Anti-drug antibodies were observed but did not appear to significantly affect the exposure to TA. Correlations between TA concentrations in plasma and brain regions in direct contact with the cisterna magna suggest glymphatic drainage may be responsible for clearance of TA from the CNS. The data support the administration of TA by isovolumetric bolus ICV infusion to pediatric patients with MPS IIIB.
摘要：
IIIB型粘多糖贮积症（MPSIIIB）是一种超级病，没有批准治疗的致命儿科疾病。它是由溶酶体酶α-N-乙酰氨基葡萄糖苷酶(NAGLU)编码基因中的突变引起的。Tralesinidasealfa（TA）是一种融合蛋白，由重组NAGLU和修饰的人胰岛素样生长因子2组成，正在开发作为MPSIIIB的酶替代疗法。由于MPSIIIB是儿科疾病的安全性/毒性，在幼年非人灵长类动物中评估了TA的药代动力学和生物分布，这些灵长类动物每周进行5次侧脑室（ICV）或单次静脉（IV）输注TA。由ICV慢速管理的TA，ICV等体积推注或静脉输注耐受性良好，在临床观察中没有观察到影响，心电图或眼科参数，或呼吸频率。观察到的药物相关变化仅限于ICV施用后CSF中和沿ICV导管轨道的细胞浸润增加。这些发现与功能变化无关，与ICV导管的使用有关。CSFPK谱在所有测试条件下是一致的,并且在ICV施用后TA广泛分布在CNS中。观察到抗药物抗体，但似乎并未显着影响对TA的暴露。血浆中TA浓度与直接与大池接触的大脑区域之间的相关性表明，淋巴引流可能是CNS中TA清除的原因。数据支持通过等体积推注ICV输注向患有MPSIIIB的儿科患者施用TA。
