Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease).
Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease).
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DOI：
10.1016/j.bbadis.2013.05.026
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Sands MS
中科院分区：
文献类型：
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作者：
Hawkins-Salsbury JA;Cooper JD;Sands MS
神经元性类脂褐质增多症(NCL，Batten病)是一组遗传性神经退行性疾病。婴儿神经元性Ceroid脂褐素沉积症(包括婴儿巴顿病或婴儿CLN1病)是由可溶性溶酶体酶棕榈酰基蛋白硫酯酶-1(PPT1)缺乏引起的，是所有NCLS中发病最早、进展最快的。几种治疗策略，包括酶替代、基因治疗、干细胞介导的治疗和小分子药物，已经导致PPT1缺乏症小鼠模型的轻微到适度的改善。然而，最近使用这些方法的各种组合的研究显示了更有希望的结果；在某些情况下，PPT1缺陷小鼠的寿命增加了一倍以上。这些针对不同致病机制的联合疗法可能为治疗这种深度神经退行性疾病提供了希望。类似的方法在治疗其他形式的NCL时可能是有用的，这些NCL是由可溶性溶酶体蛋白缺乏引起的。需要确定不同的治疗靶点并开发新的策略，以便有效地治疗因整体膜蛋白缺乏而引起的各种形式的NCL，如幼年神经元性Ceroid脂褐素沉着症。最后，所有NCLS的挑战将在于早期诊断，提高治疗效果，并有效地将其转化为临床。
The Neuronal Ceroid Lipofuscinoses (NCL, Batten Disease) are a group of inherited neurodegenerative diseases. Infantile Neuronal Ceroid lipofuscinosis (INCL, Infantile Batten Disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the life span of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as Juvenile Neuronal Ceroid Lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic.