Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model
Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model
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DOI：
10.1016/j.ymthe.2017.01.009
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发表时间：
2017-04-05
影响因子：
12.4
通讯作者：
Martin, Douglas R.
中科院分区：
文献类型：
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作者：
Gray-Edwards, Heather L.;Regier, Debra S.;Martin, Douglas R.
GM1神经节苷脂贮积症是一种致命的神经退行性疾病，影响所有年龄段的个体。在GM1小鼠和猫中使用腺相关病毒（AAV）基因治疗取得的良好结果促使人们考虑进行人体临床试验，但仍然缺乏客观的生物标志物来追踪疾病状态。我们利用血液、尿液、脑脊液（CSF）、电诊断、7T磁共振成像（MRI）和磁共振波谱技术，在未经治疗或接受AAV治疗5年以上的GM1猫中开发了一组生物标志物，并在可能的情况下将它们与人类GM1患者的标志物进行了比较。在人类和猫的GM1患者的脑脊液和血液中都发现了显著变化，猫在基因治疗后部分或完全恢复正常。基因治疗改善了GM1猫脑电图（EEG）的节律减慢，这一现象在GM1患者中也存在，但癫痫样活动仍然存在。基因治疗后，基于磁共振的分析显示大脑结构得到显著保护，与小胶质细胞增生、神经轴突丢失和脱髓鞘相关的脑代谢物得到纠正。AAV基因治疗对GM1猫具有治疗益处，许多猫在治疗后5年以上仍保持接近正常的功能，这有力地支持了对人体临床试验的深入考虑，而本文所述的生物标志物对于结果评估将是至关重要的。
GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adenoassociated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible. Significant alterations were noted in CSF and blood of GM1 humans and cats, with partial or full normalization after gene therapy in cats. Gene therapy improved the rhythmic slowing of electroencephalograms (EEGs) in GM1 cats, a phenomenon present also in GM1 patients, but nonetheless the epileptiform activity persisted. After gene therapy, MR-based analyses revealed remarkable preservation of brain architecture and correction of brain metabolites associated with microgliosis, neuroaxonal loss, and demyelination. Therapeutic benefit of AAV gene therapy in GM1 cats, many of which maintain near-normal function >5 years post-treatment, supports the strong consideration of human clinical trials, for which the biomarkers described herein will be essential for outcome assessment.