Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy.
Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy.
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DOI：
10.1016/j.omtm.2017.07.005
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Martin DR
中科院分区：
文献类型：
--
作者：
Gray-Edwards HL;Jiang X;Randle AN;Taylor AR;Voss TL;Johnson AK;McCurdy VJ;Sena-Esteves M;Ory DS;Martin DR
GM1神经节苷脂贮积症是一种致命的溶酶体疾病，目前尚无有效治疗方法。在GM1患猫中进行的腺相关病毒（AAV）基因治疗使寿命延长了6倍以上，许多猫在5.7岁以上仍然存活，且临床症状轻微。糖脂是GM1神经节苷脂贮积症中的主要贮积产物，其致病机制尚未完全明确。为了更好地确定疾病机制并为即将进行的人类临床试验确定疾病进展的标志物，进行了靶向脂质组学分析。在人道终点（约8个月）时未经治疗的GM1患猫、AAV治疗的GM1患猫（约5岁）以及正常成年对照的脑脊液中，对36种与神经节苷脂生物合成相关的鞘脂及其亚种进行了检测。在未经治疗的GM1患猫中，16种鞘脂类物质出现了显著变化，包括神经节苷脂（GM1和GM3）、乳糖酰基鞘氨醇、神经酰胺、鞘磷脂、单己糖基鞘氨醇和硫脂。许多脂质代谢物不同程度的纠正反映了AAV基因治疗的效果。鞘脂水平对神经系统疾病进展有高度预测性，11种代谢物的决定系数（R²）>0.75。此外，一种特定的去污剂添加剂显著提高了脑脊液样本中某些脂质种类的回收率。本报告展示了靶向脂质组学用于研究脂质贮积症病理生理学的方法和实用性。
GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV) gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at >5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans. 36 sphingolipids and subspecies associated with ganglioside biosynthesis were tested in the cerebrospinal fluid of untreated GM1 cats at a humane endpoint (∼8 months), AAV-treated GM1 cats (∼5 years old), and normal adult controls. In untreated GM1 cats, significant alterations were noted in 16 sphingolipid species, including gangliosides (GM1 and GM3), lactosylceramides, ceramides, sphingomyelins, monohexosylceramides, and sulfatides. Variable degrees of correction in many lipid metabolites reflected the efficacy of AAV gene therapy. Sphingolipid levels were highly predictive of neurologic disease progression, with 11 metabolites having a coefficient of determination (R2) > 0.75. Also, a specific detergent additive significantly increased the recovery of certain lipid species in cerebrospinal fluid samples. This report demonstrates the methodology and utility of targeted lipidomics to examine the pathophysiology of lipid storage disorders.
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影响因子：
12.4
作者：
Gray-Edwards, Heather L.;Regier, Debra S.;Martin, Douglas R.
通讯作者：
Martin, Douglas R.
影响因子：
120.7
作者：
Meikle, PJ;Hopwood, JJ;Carey, WF
通讯作者：
Carey, WF
影响因子：
4.8
作者：
Tagami, S;Inokuchi, J;Igarashi, Y
通讯作者：
Igarashi, Y
影响因子：
17.1
作者：
McCurdy VJ;Johnson AK;Gray-Edwards HL;Randle AN;Brunson BL;Morrison NE;Salibi N;Johnson JA;Hwang M;Beyers RJ;Leroy SG;Maitland S;Denney TS;Cox NR;Baker HJ;Sena-Esteves M;Martin DR
通讯作者：
Martin DR
DOI：
10.1073/pnas.252784899
发表时间：
2003-02-18
影响因子：
11.1
作者：
Ohmi, K;Greenberg, DS;Neufeld, EF
通讯作者：
Neufeld, EF