Gray-Edwards Heather L, Regier Debra S, Shirley Jamie L, Randle Ashley N, Salibi Nouha, Thomas Sarah E, Latour Yvonne L, Johnston Jean, Golas Gretchen, Maguire Annie S, Taylor Amanda R, Sorjonen Donald C, McCurdy Victoria J, Christopherson Peter W, Bradbury Allison M, Beyers Ronald J, Johnson Aime K, Brunson Brandon L, Cox Nancy R, Baker Henry J, Denney Thomas S, Sena-Esteves Miguel, Tifft Cynthia J, Martin Douglas R
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Ther. 2017 Apr 5;25(4):892-903. doi: 10.1016/j.ymthe.2017.01.009. Epub 2017 Feb 22.
GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated 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.
GM1神经节苷脂贮积症是一种影响各年龄段个体的致命性神经退行性疾病。在GM1小鼠和猫中使用腺相关病毒（AAV）基因治疗取得的良好效果促使人们考虑开展人体临床试验，然而，目前仍缺乏用于跟踪疾病状态的客观生物标志物。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，在未经治疗或接受AAV治疗超过5年的GM1猫中开发了一组生物标志物，并尽可能将它们与GM1人类患者的标志物进行比较。在GM1人类和猫的脑脊液和血液中发现了显著变化，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）的节律性减慢，这一现象在GM1患者中也存在，但癫痫样活动仍然持续。基因治疗后，基于磁共振成像的分析显示脑结构得到显著保留，与小胶质细胞增生、神经轴突损失和脱髓鞘相关的脑代谢物得到校正。AAV基因治疗对GM1猫具有治疗益处，其中许多猫在治疗后5年多保持接近正常的功能，这支持了对人体临床试验的深入考虑，本文所述的生物标志物对于人体临床试验的结果评估至关重要。
