Original Article

Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 499-512

First online:

Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits

  • Guilherme BaldoAffiliated withDepartment of Internal Medicine, Washington University School of MedicineGene Therapy Center, Hospital de Clinicas de Porto Alegre
  • , David F. WozniakAffiliated withDepartment of Psychiatry, Washington University School of Medicine
  • , Kevin K. OhlemillerAffiliated withDepartment of Otolaryngology, Washington University School of Medicine
  • , Yanming ZhangAffiliated withDepartment of Internal Medicine, Washington University School of Medicine
  • , Roberto GiuglianiAffiliated withGene Therapy Center, Hospital de Clinicas de Porto Alegre
  • , Katherine P. PonderAffiliated withDepartment of Internal Medicine, Washington University School of MedicineDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine Email author 

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Abstract

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.