Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Hum Gene Ther. 2012 Dec;23(12):1237-46. doi: 10.1089/hum.2012.029. Epub 2012 Oct 17.
Mucopolysaccharidosis type IIIA (MPSIIIA) is a rare lysosomal storage disorder caused by mutations in the sulfamidase gene. Accumulation of glycosaminoglycan (GAG) inside the lysosomes is associated with severe neurodegeneration as well as peripheral organ pathological changes leading to death of affected individuals during adolescence. There is no cure for MPSIIIA. Due to the limitation of the blood-brain barrier, enzyme replacement therapy and gene therapy strategies attempted thus far have not achieved whole-body correction of the disease. After the systemic administration of an adeno-associated virus 9 (AAV9) vector encoding for sulfamidase under the control of a ubiquitous promoter, we were able to obtain widespread expression of the therapeutic transgene in brain and in peripheral organs, and sulfamidase activity in serum of both male and female MPSIIIA mice. This was accompanied by the normalization of GAG storage levels in most peripheral organs. In brain, decrease in GAG tissue content following AAV9 gene transfer of sulfamidase was associated with the resolution of neuroinflammation. Finally, correction of disease phenotype resulted in a remarkable prolongation of survival of both male and female AAV-treated MPSIIIA mice. This proof-of-concept study will be relevant to the future development of therapies for MPSIIIA.
III 型黏多糖贮积症（MPSIIIA）是一种罕见的溶酶体贮积症，由磺酰胺酶基因的突变引起。糖胺聚糖（GAG）在溶酶体内的积累与严重的神经退行性变以及周围器官的病理变化有关，导致受影响的个体在青少年时期死亡。目前还没有治疗 MPSIIIA 的方法。由于血脑屏障的限制，迄今为止尝试的酶替代疗法和基因治疗策略都未能实现全身性纠正疾病。在全身给予编码磺酰胺酶的腺相关病毒 9（AAV9）载体后，我们能够在大脑和外周器官中广泛表达治疗性转基因，并且在雄性和雌性 MPSIIIA 小鼠的血清中都有磺酰胺酶活性。这伴随着大多数外周器官中 GAG 储存水平的正常化。在大脑中，磺酰胺酶的 AAV9 基因转移后 GAG 组织含量的减少与神经炎症的消退有关。最后，疾病表型的纠正导致雄性和雌性 AAV 治疗的 MPSIIIA 小鼠的存活时间显著延长。这项概念验证研究将与 MPSIIIA 的未来治疗方法的发展相关。
