Different serum enzyme levels are required to rescue the various systemic features of the mucopolysaccharidoses.
Mucopolysaccharidoses (MPSs) are lysosomal storage disorders characterized by progressive accumulation of glycosaminoglycans (GAGs) in various tissues. Enzyme replacement therapy (ERT) for several MPSs is available to date. However, the efficacy of ERT is limited, in particular in compartments such as bone, cartilage, the brain, and the eyes. We selected a rodent model of an MPS, with no central nervous system storage, to study the impact, on systemic features of the disease, of various stable levels of exogenous enzymes produced by adeno-associated viral vector (AAV)-mediated liver gene transfer. Low levels (6% of normal) of circulating enzyme were enough to reduce storage and inflammation in the visceral organs and to ameliorate skull abnormalities; intermediate levels (11% of normal) were required to reduce urinary GAG excretion; and high levels (>or=50% of normal) rescued abnormalities of the long bones and motor activity. These data will be instrumental to design appropriate clinical protocols based on either enzyme or gene replacement therapy for MPS and to predict their impact on the pathological features of MPS.
Cotugno
Gabriella
G
Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy.
Tessitore
Alessandra
A
Capalbo
Anita
A
Annunziata
Patrizia
P
Strisciuglio
Caterina
C
Faella
Armida
A
Aurilio
Michela
M
Di Tommaso
Maurizio
M
Russo
Fabio
F
Mancini
Antonio
A
De Leonibus
Elvira
E
Aloj
Luigi
L
Auricchio
Alberto
A
D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D001921:Brain / Q000473:pathology; D002356:Cartilage / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology; D056947:Enzyme Replacement Therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D006025:Glycosaminoglycans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D016464:Lysosomal Storage Diseases / Q000473:pathology; D009083:Mucopolysaccharidoses / Q000473:pathology*; D051381:Rats
D006025:Glycosaminoglycans