Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate
Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate
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DOI：
10.1007/8904_2013_226
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发表时间：
2013-01-01
期刊：
影响因子：
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通讯作者：
Velinov, M.
中科院分区：
文献类型：
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作者：
Gavin, M.;Wen, G. Y.;Velinov, M.
基因CLN 1中的纯合突变通常导致癫痫发作的神经元蜡样质脂褐质沉积症，这是一种严重的进行性神经系统疾病，伴有早期死亡。基因CLN 1编码棕榈酰蛋白硫酯酶（PPT 1），参与S-脂肪酰化蛋白的溶酶体降解。半胱胺酒石酸氢盐（Cystagon）已显示减少PPT 1缺陷细胞中的储存材料。我们报告了一项为期7年的、开放标签的、非随机试验的结果，该试验使用Cystagon治疗4例由轻度CLN 1突变引起的青少年NCL。Cystagon剂量逐渐增加，目标是达到50 mg/kg体重。在4名接受治疗的个体和5名未接受治疗的具有相同CLN 1突变的对照中，通过父母问卷监测疾病进展。检查给药个体的单核细胞白细胞的亚显微镜下溶酶体贮积包涵体。半胱氨酸蛋白酶抑制剂治疗导致治疗个体的外周白细胞中的储存物质减少。未发现严重副作用。其中1例患者发生过敏性皮疹，需要降低剂量。治疗未导致疾病进展的总体减弱。当对其中两个人进行单独分析时，观察到疾病进展较慢。然而，在开始治疗前，也观察到这些个体的进展较慢。这种效应可能是由于该组中达到的更高的Cystagon剂量，但也可能是巧合。Cystagon明显缺乏毒性，可能需要在婴儿NCL中进行进一步的Cystagon试验，可能与其他开发中的疗法联合使用。
Homozygous mutations in the gene CLN1 typically result in infantile-onset neuronal ceroid lipofuscinosis, a severe progressive neurological disorder with early death. The gene CLN1 encodes the enzyme palmitoyl protein thioesterase (PPT1), which is involved in lysosomal degradation of S-fatty acylated proteins. Cysteamine bitartrate (Cystagon) has been shown to reduce the storage material in PPT1 deficient cells. We report the results of a 7-year, open label, nonrandomized trial using Cystagon in four individuals with juvenile-onset NCL resulting from milder CLN1 mutations. The Cystagon doses were gradually increased with the goal of achieving 50 mg/kg bodyweight. The disease progression was monitored with parental questionnaires in four treated individuals and five untreated controls with the same CLN1 mutations. Mononuclear leukocytes from the treated individuals were examined for submicroscopic lysosomal storage inclusions. Cystagon treatment resulted in decreased storage material in peripheral leukocytes of the treated individuals. No severe side effects were noted. An allergic rash occurred in one of the individuals that required a dose reduction. The treatment did not result in overall attenuation of the disease progression. Slower progression of the disease was observed in two of the individuals when they were analyzed separately. However, slower progression in these individuals was also observed prior to starting the treatment. This effect may have been due to the higher Cystagon dose achieved in this group, but it could also have been coincidental. The apparent lack of toxicity of Cystagon may warrant further Cystagon trials in infantile NCL, possibly in conjunction with other developing therapies.