食蟹猴脑室内重复给药 CPI-601（重组人棕榈酰蛋白硫酯酶-1）的安全性、药代动力学与剂量选择
Intracerebroventricular repeat dose CPI-601 recombinant human palmitoyl-protein thioesterase-1 in cynomolgus monkey: safety, pharmacokinetics, and dose selection
CLN1 巴顿病由 CLN1 基因突变引起，导致患儿认知、语言、运动倒退、癫痫和失明，目前除姑息治疗外无获批疗法。CPI-601 是一种重组人棕榈酰蛋白硫酯酶-1，作为酶替代疗法（补充患者缺失的酶）经脑室内（直接注入脑室）给药。研究在幼年食蟹猴中开展规范的重复给药毒理和药代动力学试验，脑脊液中药物约 0.5 小时达峰，暴露随剂量增加，全身暴露有限，未检出抗药抗体。最高剂量下出现轻度至中度的显微神经病理改变。该结果为后续儿科临床试验的剂量选择提供依据。
为什么推荐给您：新酶替代疗法的非人灵长类毒理与剂量研究，属推动首次儿科试验转化的必要步骤，尚无人体数据
不需要生物学背景，多打比方
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摘要Abstract
CLN1 Batten Disease is caused by mutations in the CLN1 gene resulting in a reduction or absence of enzyme activity. It is characterized by progressive cognitive, language and motor regression, seizures, loss of vision, and early death. There is currently no approved treatment for this rare disease apart from palliative care. Recombinant human palmitoyl-protein thioesterase-1 (rhPPT1, CPI-601) can be used as an enzyme replacement therapy (ERT) for CLN1. A good laboratory practice (GLP) repeat-dose toxicology and pharmacokinetic study was conducted in juvenile cynomolgus monkeys following intracerebroventricular (ICV) administration of CPI-601 to support clinical translation based on efficacy data seen in the CLN1-/- mouse preclinical efficacy model. Safety assessments included clinical observations, neurologic evaluations, clinical pathology, electrocardiography, ophthalmology, anti-drug antibody (ADA) analysis, pharmacokinetics, and comprehensive neuropathology. CPI-601 demonstrated rapid cerebrospinal fluid (CSF) exposure with peak concentrations observed approximately 0.5 h following administration. Exposure increased with dose, while systemic exposure remained limited. In CLN1 patient fibroblasts, CPI-601 exhibited a half-life of 21.38 h. No anti-drug antibodies (ADAs) were detected during the study. No treatment-related changes were observed in body weight, electrocardiography, ophthalmology, respiratory parameters, or clinical pathology. No comparable adverse findings were observed at lower dose levels. There were microscopic findings only at the highest dose tested, that were minor to moderate in nature and progressed from minimal microgliosis at the end of dosing to moderate neurodegenerative changes during recovery. This study now supports dosing of CPI-601 ICV in a pediatric clinical trial for which allometric scaling was used to enable dose selection. ONE SENTENCE SUMMARY: Safety evaluation and pharmacokinetics of CPI-601 as an enzyme replacement therapy for CLN1 Batten disease in non-human primates.