Premium
Retroviral‐vector‐mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits
Author(s) -
Baldo Guilherme,
Wozniak David F.,
Ohlemiller Kevin K.,
Zhang Yanming,
Giugliani Roberto,
Ponder Katherine P.
Publication year - 2013
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-012-9530-x
Subject(s) - mucopolysaccharidosis i , genetic enhancement , mucopolysaccharidosis , viral vector , lysosomal storage disease , vector (molecular biology) , mucopolysaccharidosis type i , medicine , endocrinology , immunology , gene , biology , enzyme replacement therapy , disease , biochemistry , recombinant dna
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to α‐L‐iduronidase (IDUA) deficiency that results in the accumulation of glycosaminoglycans (GAG). Systemic gene therapy to MPS I mice can reduce lysosomal storage in the brain, but few data are available regarding the effect upon behavioral function. We investigated the effect of gene therapy with a long‐terminal‐repeat (LTR)‐intact retroviral vector or a self‐inactivating (SIN) vector on behavioral function in MPS I mice. The LTR vector was injected intravenously to 6‐week‐old MPS I mice, and the SIN vector was given to neonatal or 6‐week‐old mice. Adult‐LTR, neonatal‐SIN, and adult‐SIN‐treated mice achieved serum IDUA activity of 235 ± 20 (84‐fold normal), 127 ± 10, and 71 ± 7 U/ml, respectively. All groups had reduction in histochemical evidence of lysosomal storage in the brain, with the adult‐LTR group showing the best response, while adult‐LTR mice had reductions in lysosomal storage in the cristae of the vestibular system. Behavioral evaluation was performed at 8 months. Untreated MPS I mice had a markedly reduced ability to hold onto an inverted screen or climb down a pole. LTR‐vector‐treated mice had marked improvements on both of these tests, whereas neonatal‐SIN mice showed improvement in the pole test. We conclude that both vectors can reduce brain disease in MPS I mice, with the LTR vector achieving higher serum IDUA levels and better correction. Vestibular abnormalities may contribute to mobility problems in patients with MPS I, and gene therapy may reduce symptoms.