Correction of CNS defects in the MPSII mouse model via systemic enzyme replacement therapy.
Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, is a devastating disorder associated with a shortened life expectancy. Patients affected by MPSII have a variety of symptoms that affect all organs of the body and may include progressive cognitive impairment. MPSII is due to inactivity of the enzyme iduronate-2-sulfatase (IDS), which results in the accumulation of storage material in the lysosomes, such as dermatan and heparan sulfates, with consequent cell degeneration in all tissues including, in the severe phenotype, neurodegeneration in the central nervous system (CNS). To date, the only treatment available is systemic infusion of IDS, which ameliorates exclusively certain visceral defects. Therefore, it is important to simultaneously treat the visceral and CNS defects of the MPSII patients. Here, we have developed enzyme replacement therapy (ERT) protocols in a mouse model that allow the IDS to reach the brain, with the substantial correction of the CNS phenotype and of the neurobehavioral features. Treatments were beneficial even in adult and old MPSII mice, using relatively low doses of infused IDS over long intervals. This study demonstrates that CNS defects of MPSII mice can be treated by systemic ERT, providing the potential for development of an effective treatment for MPSII patients.
Polito
Vinicia Assunta
VA
Telethon Institute of Genetics and Medicine (TIGEM), CNR, via P. Castellino 111, Naples 80131, Italy.
Abbondante
Serena
S
Polishchuk
Roman S
RS
Nusco
Edoardo
E
Salvia
Rosaria
R
Cosma
Maria Pia
MP
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D006025:Glycosaminoglycans / Q000378:metabolism; D007066:Iduronate Sulfatase / Q000097:blood / Q000627:therapeutic use*; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D016532:Mucopolysaccharidosis II / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D009928:Organ Specificity; D045442:Rotarod Performance Test
D006025:Glycosaminoglycans; D007066:Iduronate Sulfatase