Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin
Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin
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DOI：
10.1073/pnas.96.11.6388
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发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
Platt, FM
中科院分区：
文献类型：
--
作者：
Jeyakumar, M;Butters, TD;Platt, FM
桑德霍夫病是一种神经退行性疾病，由 HEXB 基因突变引起，该基因编码 P-己糖胺酶的 P 亚基，G(M2) 神经节苷脂无法降解并在外周和中枢神经系统 (CNS) 细胞的溶酶体中积聚，目前尚无治疗方法 涉及中枢神经系统病理学的鞘糖脂溶酶体贮积病，包括 G(M2) 神经节苷脂贮积症。治疗这种疾病和相关疾病的一种策略是底物剥夺，这将利用糖鞘脂生物合成的抑制剂来平衡合成与分解代谢速率受损，从而防止储存，其中一种抑制剂是 N-丁基脱氧野尻霉素，目前正在进行潜在治疗 1 型戈谢病的临床试验，戈谢病是一种相关疾病，涉及 鞘糖脂储存在外周组织中，但不储存在中枢神经系统中。在这项研究中，我们评估了该药物是否也可以应用于治疗中枢神经系统储存和病理学疾病。因此，我们用抑制剂 N-丁基脱氧野尻霉素治疗了桑德霍夫病小鼠模型。接受治疗的小鼠症状出现延迟，大脑和周围组织的储存减少，预期寿命延长。因此，底物剥夺为这一类溶酶体贮积病（包括患有中枢神经系统疾病的疾病）提供了一种潜在的通用疗法。
Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the P-subunit of P-hexosaminidase, G(M2) ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS), There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the G(M2) gangliosidoses. One strategy for treating this and related diseases is substrate deprivation, This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage, One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS, In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease.