Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits
- First Online:
- 387 Downloads
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.
- Fuller GN, Burger PC (2007) Central nervous system. In: Mills S (ed) Histology for Pathologists, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 273–319Google Scholar
- Neufeld EF, Muenzer J (2001) The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York, pp 3421–3452Google Scholar
- Ohlemiller KK, Hennig AK, Lett JM, Heidbreder AF, Sands MS (2002) Inner ear pathology in the mucopolysaccharidosis VII mouse. Hear Res 16:969–984Google Scholar