Liver-directed gene therapy corrects neurologic disease in a murine model of mucopolysaccharidosis type I-Hurler
Xiu Jin, Jing Su, Qinyu Zhao, Ruiting Li, Jianlu Xiao, Xiaomei Zhong, Li Song, Yi Liu, Kaiqin She, Hongxin Deng, Yuquan Wei, Yang Yang
Abstract
. Then, liver-directed gene therapy using the adeno-associated virus 8 (AAV8) vector, which encoded the modified hIDUA cDNA driven by a liver-specific expression cassette was evaluated in an adult MPS I-H mouse model. The results showed that intravenous (i.v.) infusion of AAV8 resulted in sustained supraphysiological levels of IDUA activity and normalized glycosaminoglycan (GAG) accumulation in peripheral tissues. Addition of MTfp to the hIDUA N terminus allowed efficient BBB transcytosis and IDUA activity restoration in the brain, resulting in significant improvements in brain pathology and neurobehavioral deficits. Our results provide a novel strategy to develop minimally invasive therapies for treatment of MPS I-H and other neurodegenerative LSDs.