Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation

Xin Chen, Sarah Snanoudj-Verber, Laura Pollard, Yuhui Hu, Sara S. Cathey, Ritva Tikkanen, Steven J. Gray

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)989-1000
Number of pages12
JournalMolecular Therapy
Volume29
Issue number3
DOIs
StatePublished - Mar 3 2021

Keywords

  • AAV
  • AGA
  • AGU
  • CNS
  • adeno-associated virus
  • aspartylglucosaminidase
  • aspartylglucosaminuria
  • central nervous system
  • gene therapy
  • lysosomal storage disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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