Preclinical dose-finding study with a liver-tropic, recombinant AAV-2/8 vector in the mouse model of galactosialidosis

Huimin Hu, Elida Gomero, Erik Bonten, John T. Gray, Jim Allay, Yanan Wu, Jianrong Wu, Christopher Calabrese, Arthur Nienhuis, Alessandra D'Azzo

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients.

Original languageEnglish
Pages (from-to)267-274
Number of pages8
JournalMolecular Therapy
Issue number2
StatePublished - Feb 2012

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (DK52025, GM60905), the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital. A. d'A. holds an endowed chair in Genetics and Gene Therapy from the Jewelry Charity Fund. The authors wish to thank Pat Streich for her assistance in preparing the manuscript.

ASJC Scopus subject areas

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


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