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 - 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
SN - 1525-0016
VL - 29
SP - 989
EP - 1000
JO - Molecular Therapy
JF - Molecular Therapy
IS - 3
ER -