Long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer.
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.
Telethon Institute of Genetics and Medicine, Naples, Italy.
Gabriella
G
Cotugno
Patrizia
P
Annunziata
Alessandra
A
Tessitore
Thomas
T
O'Malley
Anita
A
Capalbo
Armida
A
Faella
Rosa
R
Bartolomeo
Patricia
P
O'Donnell
Ping
P
Wang
Fabio
F
Russo
Meg M
MM
Sleeper
Van W
VW
Knox
Steven
S
Fernandez
Leah
L
Levanduski
John
J
Hopwood
Elvira
E
De Leonibus
Mark
M
Haskins
Alberto
A
Auricchio
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002415:Cats; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006025:Glycosaminoglycans / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009087:Mucopolysaccharidosis VI / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D016896:Treatment Outcome
D006025:Glycosaminoglycans; D020051:N-Acetylgalactosamine-4-Sulfatase