Long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer.

Abstract

Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 10(13) genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 10(12) gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.

• Authors: Gabriella Cotugno, Patrizia Annunziata, Alessandra Tessitore, Thomas O'Malley, Anita Capalbo, Armida Faella, Rosa Bartolomeo, Patricia O'Donnell, Ping Wang, Fabio Russo, Meg M Sleeper, Van W Knox, Steven Fernandez, Leah Levanduski, John Hopwood, Elvira De Leonibus, Mark Haskins, Alberto Auricchio
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 3 Pg. 461-9 (Mar 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21119624 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glycosaminoglycans
• N-Acetylgalactosamine-4-Sulfatase

Topics

• Animals
• Bone and Bones (metabolism, pathology)
• Cats
• Dependovirus (genetics)
• Gene Expression Regulation (drug effects, genetics)
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics)
• Glycosaminoglycans (metabolism)
• HEK293 Cells
• Humans
• Liver (metabolism)
• Motor Activity (drug effects, genetics)
• Mucopolysaccharidosis VI (enzymology, pathology, therapy)
• N-Acetylgalactosamine-4-Sulfatase (genetics, metabolism)
• Phenotype
• Treatment Outcome