1 Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, Alabama.
2 Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts.
Hum Gene Ther. 2018 Mar;29(3):312-326. doi: 10.1089/hum.2017.163. Epub 2017 Sep 18.
Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α + β) injected at high (1.3 × 10 vector genomes) or low (4.2 × 10 vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + β), and ganglioside clearance was most widespread in the TSD α + β high-dose sheep. Microglial activation and proliferation in TSD sheep-most prominent in the cerebrum-were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.
泰萨二氏病（TSD）是一种致命的神经退行性疾病，由己糖胺酶 A（HexA）缺乏引起。TSD 也发生在绵羊中，这是唯一具有疾病临床症状的 TSD 实验模型。使用连续的神经学评估、7 特斯拉磁共振成像、超声心动图、电诊断和脑脊液生物标志物来描述绵羊 TSD 的自然病史。还使用 AAVrh8 单顺反子载体对颅内基因治疗进行了测试，这些载体编码 Hex 的 α 亚基（TSD α）或分别编码 α 和 β 亚基的两种载体的混合物（TSD α + β），以高（1.3×10 载体基因组）或低（4.2×10 载体基因组）剂量注射。在所有接受腺相关病毒治疗的绵羊中，都观察到症状发作的延迟和/或获得性症状的减少。尸检评估显示，与 TSD α 绵羊相比，TSD α + β 绵羊的大脑中 HexA 和载体基因组分布更好，但所有组的脊髓分布都很低。同工酶分析表明，两种载体（TSD α + β）治疗后的 HexA 形成更好，高剂量 TSD α + β 绵羊的神经节苷脂清除最广泛。基因治疗后，TSD 绵羊的小胶质细胞激活和增殖（在大脑中最为明显）减弱。本报告证明了 TSD 在绵羊大脑中的治疗效果，其与儿童大脑的效果相当。
