Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus-α-L-Iduronidase for Hurler Disease.
| Autor: | Janson CG; Department of Neurosurgery, ‡Department of Neurology, ¶Department of Medicine, and ‖Genetics and Cell Biology, University of Minnesota, School of Medicine §Cell & Gene Therapy Center, University of Medicine and Dentistry of New Jersey School of Medicine., Romanova LG, Leone P, Nan Z, Belur L, McIvor RS, Low WC |
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| Jazyk: | angličtina |
| Zdroj: | Neurosurgery [Neurosurgery] 2014 Jan; Vol. 74 (1), pp. 99-111. |
| DOI: | 10.1227/NEU.0000000000000157 |
| Abstrakt: | Background: Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations. Objective: To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks. Methods: Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface. Results: Intraventricular delivery of 1 × 10 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 10 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods. Conclusion: Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere. |
| Databáze: | MEDLINE |
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