Abstract |
Enzyme replacement therapy has revolutionized the treatment of the somatic manifestations of lysosomal storage diseases ( LSD), although it has been ineffective in treating central nervous system (CNS) manifestations of these disorders. The development of neurotrophic vectors based on novel serotypes of adeno-associated viruses (AAV) such as AAV9 provides a potential platform for stable and efficient delivery of enzymes to the CNS. We evaluated the safety and efficacy of intrathecal delivery of AAV9 expressing α-l- iduronidase (IDUA) in a previously described feline model of mucopolysaccharidosis I (MPS I). A neurological phenotype has not been defined in these animals, so our analysis focused on the biochemical and histological CNS abnormalities characteristic of MPS I. Five MPS I cats were dosed with AAV9 vector at 4-7 months of age and followed for 6 months. Treated animals demonstrated virtually complete correction of biochemical and histological manifestations of the disease throughout the CNS. There was a range of antibody responses against IDUA in this cohort which reduced detectable enzyme without substantially reducing efficacy; there was no evidence of toxicity. This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic.
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Authors | Christian Hinderer, Peter Bell, Brittney L Gurda, Qiang Wang, Jean-Pierre Louboutin, Yanqing Zhu, Jessica Bagel, Patricia O'Donnell, Tracey Sikora, Therese Ruane, Ping Wang, Mark E Haskins, James M Wilson |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 22
Issue 12
Pg. 2018-2027
(Dec 2014)
ISSN: 1525-0024 [Electronic] United States |
PMID | 25027660
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Animals
- Cats
- Central Nervous System
(pathology)
- Dependovirus
(enzymology, genetics)
- Disease Models, Animal
- Genetic Therapy
(methods)
- Genetic Vectors
(administration & dosage)
- Iduronidase
(blood, cerebrospinal fluid)
- Injections, Spinal
- Mucopolysaccharidosis I
(enzymology, genetics, pathology, therapy)
- Organ Specificity
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