TY - JOUR
T1 - Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation
AU - Chen, Xin
AU - Snanoudj-Verber, Sarah
AU - Pollard, Laura
AU - Hu, Yuhui
AU - Cathey, Sara S.
AU - Tikkanen, Ritva
AU - Gray, Steven J.
N1 - Funding Information:
This study was supported by the Rare Trait Hope Fund (USA) , the UNC TraCS Institute (USA, 550KR121511), and AFM-Téléthon (France, Award 19715) to S.J.G. We thank Jackson Laboratories for providing the AGA +/− breeders, the UNC Vector Core facility for producing some vectors used in these studies, and Greenwood Genetics Center for performing the AGA substrate assays. We thank the members at the UNC Center for Animal MRI (CAMRI) and Biomedical Research Imaging Center (BRIC) for technical assistance, supported in part by the Bowles Center for Alcohol Studies ( P60 AA011605 ), the Lineberger Comprehensive Center ( P30 CA016086 ), and the Carolina Institute for Developmental Disabilities ( U54 HD079124 ). We also acknowledge Dr. Thomas Dong for his help in sample preparation, Dr. Mary Wight-Carter for her toxicity evaluation and histopathological safety report, Dr. Anna Azvolinsky for her support in manuscript preparation, and Dr. Stuart Cobb for his insightful manuscript review.
Funding Information:
This study was supported by the Rare Trait Hope Fund (USA), the UNC TraCS Institute(USA, 550KR121511), and AFM-T?l?thon (France, Award 19715) to S.J.G. We thank Jackson Laboratories for providing the AGA+/? breeders, the UNC Vector Core facility for producing some vectors used in these studies, and Greenwood Genetics Center for performing the AGA substrate assays. We thank the members at the UNC Center for Animal MRI (CAMRI) and Biomedical Research Imaging Center (BRIC) for technical assistance, supported in part by the Bowles Center for Alcohol Studies (P60 AA011605), the Lineberger Comprehensive Center (P30 CA016086), and the Carolina Institute for Developmental Disabilities (U54 HD079124). We also acknowledge Dr. Thomas Dong for his help in sample preparation, Dr. Mary Wight-Carter for her toxicity evaluation and histopathological safety report, Dr. Anna Azvolinsky for her support in manuscript preparation, and Dr. Stuart Cobb for his insightful manuscript review. X.C. and S.J.G. designed the experiments, coordinated studies with collaborators and core facilities, and wrote the manuscript. X.C. S.S.-V. L.P. and Y.H. performed the experiments. S.S.C. served as a consultant on this project. X.C. analyzed all data and prepared all figures for the manuscript. L.P. and Y.H. helped writing the Materials and Methods section. R.T. advised the project, shared protocols, and reviewed the manuscript. S.J.G. oversaw all activities related to the project and acquired all funding for the work. S.J.G. has received patent royalties for intellectual property (IP) licensed to Asklepios Biophama, but this IP was not used in this study. S.J.G. is an inventor of the AGA vector design and has received patent royalties on this technology from Neurogene.
Publisher Copyright:
© 2020
PY - 2021/3/3
Y1 - 2021/3/3
N2 - Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by loss of the enzyme aspartylglucosaminidase (AGA), resulting in AGA substrate accumulation. AGU patients have a slow but progressive neurodegenerative disease course, for which there is no approved disease-modifying treatment. In this study, AAV9/AGA was administered to Aga−/− mice intravenously (i.v.) or intrathecally (i.t.), at a range of doses, either before or after disease pathology begins. At either treatment age, AAV9/AGA administration led to (1) dose dependently increased and sustained AGA activity in body fluids and tissues; (2) rapid, sustained, and dose-dependent elimination of AGA substrate in body fluids; (3) significantly rescued locomotor activity; (4) dose-dependent preservation of Purkinje neurons in the cerebellum; and (5) significantly reduced gliosis in the brain. Treated mice had no abnormal neurological phenotype and maintained body weight throughout the whole experiment to 18 months old. In summary, these results demonstrate that treatment of Aga−/− mice with AAV9/AGA is effective and safe, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation. Further, we provide a direct comparison of the efficacy of an i.v. versus i.t. approach using AAV9, which should greatly inform the development of similar treatments for other related lysosomal storage diseases. Reported results demonstrated the effectiveness and safety of AAV9/AGA in Aga−/− mice, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation. Moreover, the direct comparison of the efficacy of an intravenous versus intrathecal approach should greatly inform the development of similar treatments for other related disorders.
AB - Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease caused by loss of the enzyme aspartylglucosaminidase (AGA), resulting in AGA substrate accumulation. AGU patients have a slow but progressive neurodegenerative disease course, for which there is no approved disease-modifying treatment. In this study, AAV9/AGA was administered to Aga−/− mice intravenously (i.v.) or intrathecally (i.t.), at a range of doses, either before or after disease pathology begins. At either treatment age, AAV9/AGA administration led to (1) dose dependently increased and sustained AGA activity in body fluids and tissues; (2) rapid, sustained, and dose-dependent elimination of AGA substrate in body fluids; (3) significantly rescued locomotor activity; (4) dose-dependent preservation of Purkinje neurons in the cerebellum; and (5) significantly reduced gliosis in the brain. Treated mice had no abnormal neurological phenotype and maintained body weight throughout the whole experiment to 18 months old. In summary, these results demonstrate that treatment of Aga−/− mice with AAV9/AGA is effective and safe, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation. Further, we provide a direct comparison of the efficacy of an i.v. versus i.t. approach using AAV9, which should greatly inform the development of similar treatments for other related lysosomal storage diseases. Reported results demonstrated the effectiveness and safety of AAV9/AGA in Aga−/− mice, providing strong evidence that AAV9/AGA gene therapy should be considered for human translation. Moreover, the direct comparison of the efficacy of an intravenous versus intrathecal approach should greatly inform the development of similar treatments for other related disorders.
KW - AAV
KW - AGA
KW - AGU
KW - CNS
KW - adeno-associated virus
KW - aspartylglucosaminidase
KW - aspartylglucosaminuria
KW - central nervous system
KW - gene therapy
KW - lysosomal storage disease
UR - http://www.scopus.com/inward/record.url?scp=85097368055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097368055&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2020.11.012
DO - 10.1016/j.ymthe.2020.11.012
M3 - Article
C2 - 33186692
AN - SCOPUS:85097368055
VL - 29
SP - 989
EP - 1000
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 3
ER -