Acetyl-leucine slows disease progression in lysosomal storage disorders.
Acetyl-leucine slows disease progression in lysosomal storage disorders.
复制标题
乙酰亮氨酸减缓溶酶体贮积症的疾病进展。
DOI：
10.1093/braincomms/fcaa148
复制
发表时间：
2021
影响因子：
4.8
通讯作者：
Platt FM
中科院分区：
文献类型：
--
作者：
Kaya E;Smith DA;Smith C;Morris L;Bremova-Ertl T;Cortina-Borja M;Fineran P;Morten KJ;Poulton J;Boland B;Spencer J;Strupp M;Platt FM
乙酰亮氨酸是支链氨基酸亮氨酸的衍生物。在观察性临床研究中，乙酰-dl-亮氨酸可改善共济失调症状，尤其是溶酶体贮积障碍（Niemann-Pick病C1型）患者。在这里，我们研究了乙酰-dl-亮氨酸及其对映体乙酰-l-亮氨酸和乙酰-d-亮氨酸在症状性Npc1 - / -小鼠中的作用，并观察到单个对映体和乙酰-dl-亮氨酸对失调的改善。当症状前给予Npc1 - / -小鼠乙酰-l-亮氨酸和乙酰-l-亮氨酸时，两种治疗均可延缓疾病进展并延长寿命，而乙酰-d-亮氨酸则没有。这些数据与乙酰亮氨酸是神经保护对映体的观点一致。葡萄糖和抗氧化代谢的改变是Npc1 - / -小鼠中l-对映体作用的潜在机制之一。当护理标准药物米卢司他与乙酰亮氨酸联合使用时，有显著的协同作用。与这些临床前数据一致，当Niemann-Pick病C1型患者在接受乙酰-dl-亮氨酸治疗12个月后进行评估时，疾病进展速度减慢，多个神经系统稳定或改善。在本研究中，在GM2神经节脂质病（Sandhoff病）小鼠模型以及Tay-Sachs和Sandhoff病个例的超说明书用药中，乙酰-dl-亮氨酸对步态的有益影响也被观察到。综上所述，我们已经确定了乙酰-l-亮氨酸在溶酶体积存疾病中的意想不到的神经保护作用和潜在的作用机制，支持其在溶酶体疾病的临床试验中的进一步评估。本研究在小鼠模型和临床研究中探讨了乙酰- dl -亮氨酸在两种不同病因的神经退行性溶酶体贮积病（Niemann-Pick C型和GM2神经节脂质沉积症）中的疾病改善作用。乙酰- dl -亮氨酸及其L对映体可能通过改变代谢提供神经保护-这是治疗这些疾病的新方法。
Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1−/− mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1−/− mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1−/− mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders. This study investigates the disease-modifying effect of acetyl-DL-leucine in two neurodegenerative lysosomal storage diseases with different aetiologies: Niemann-Pick type C and GM2 gangliosidosis in both murine models and clinical studies. Acetyl-DL-leucine and its L enantiomer provide neuroprotection likely by altering metabolism – a new therapeutic approach for these diseases.
登录
查看更多内容
影响因子：
--
作者：
da Veiga Moreira J;Peres S;Steyaert JM;Bigan E;Paulevé L;Nogueira ML;Schwartz L
通讯作者：
Schwartz L
影响因子：
3.7
作者：
Günther L;Beck R;Xiong G;Potschka H;Jahn K;Bartenstein P;Brandt T;Dutia M;Dieterich M;Strupp M;la Fougère C;Zwergal A
通讯作者：
Zwergal A
影响因子：
3.7
作者：
Kennedy BE;LeBlanc VG;Mailman TM;Fice D;Burton I;Karakach TK;Karten B
通讯作者：
Karten B
DOI：
10.1016/j.str.2008.10.010
发表时间：
2008-12-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Kato M;Wynn RM;Chuang JL;Tso SC;Machius M;Li J;Chuang DT
通讯作者：
Chuang DT
影响因子：
5.3
作者：
Jha, Mithilesh Kumar;Jeon, Sangmin;Suk, Kyoungho
通讯作者：
Suk, Kyoungho