Abstract
Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.
| Original language | English |
|---|---|
| Pages (from-to) | 310-316 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 7 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2001 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors : Correction of neuropathology and protection against learning impairments in affected mice. / Consiglio, Antonella; Quattrini, Angelo; Martino, Sabata; Bensadoun, Jean Charles; Dolcetta, Diego; Trojani, Alessandra; Benaglia, Giuliana; Marchesini, Sergio; Cestari, Vincenzo; Oliverio, Alberto; Bordignon, Claudio; Naldini, Luigi.
In: Nature Medicine, Vol. 7, No. 3, 2001, p. 310-316.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors
T2 - Correction of neuropathology and protection against learning impairments in affected mice
AU - Consiglio, Antonella
AU - Quattrini, Angelo
AU - Martino, Sabata
AU - Bensadoun, Jean Charles
AU - Dolcetta, Diego
AU - Trojani, Alessandra
AU - Benaglia, Giuliana
AU - Marchesini, Sergio
AU - Cestari, Vincenzo
AU - Oliverio, Alberto
AU - Bordignon, Claudio
AU - Naldini, Luigi
PY - 2001
Y1 - 2001
N2 - Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.
AB - Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.
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U2 - 10.1038/85454
DO - 10.1038/85454
M3 - Article
VL - 7
SP - 310
EP - 316
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 3
ER -