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.
|Number of pages||8|
|State||Published - Feb 2012|
Bibliographical noteFunding 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
- Drug Discovery