Walia Jagdeep S, Altaleb Naderah, Bello Alexander, Kruck Christa, LaFave Matthew C, Varshney Gaurav K, Burgess Shawn M, Chowdhury Biswajit, Hurlbut David, Hemming Richard, Kobinger Gary P, Triggs-Raine Barbara
1] Department of Pediatrics, Queen's University, Kingston, Ontario, Canada [2] Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada [3] Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Manitoba, Canada [4] Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.
Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Mol Ther. 2015 Mar;23(3):414-22. doi: 10.1038/mt.2014.240. Epub 2014 Dec 17.
G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum β-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, β-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain β-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy.
GM2神经节苷脂沉积症是由于β-己糖胺酶A活性缺乏导致的严重神经退行性疾病，且缺乏有效的治疗方法。我们使用GM2神经节苷脂沉积症的Sandhoff病（SD）小鼠模型（Hexb-/-），测试了全身递送表达Hexb cDNA的腺相关病毒9（AAV9）纠正神经表型的潜力。对新生或成年的SD小鼠和正常小鼠静脉注射AAV9-HexB或-LacZ，并监测血清β-己糖胺酶活性、运动功能和存活率。在实验第43周或更早的人道终点评估脑GM2神经节苷脂、β-己糖胺酶活性和炎症。注射AAV9-LacZ的SD小鼠在17周龄时死亡，而所有新生期接受AAV9-HexB治疗的SD小鼠均存活至43周（P<0.0001），只有3只表现出神经功能障碍。成年期接受AAV9-HexB治疗的SD小鼠在17至35周之间死亡。与成年期接受AAV9-HexB和SD-LacZ治疗的组相比，新生期接受SD-HexB治疗的小鼠脑β-己糖胺酶活性显著增加，GM2神经节苷脂蓄积和神经炎症减少。然而，在43周时，10只新生期注射HexB的对照小鼠和SD小鼠中有8只出现肝或肺肿瘤。这项研究证明了通过早期基于rAAV9的全身基因治疗长期纠正SD和其他GM2神经节苷脂沉积症的潜力。
