Format

Send to

Choose Destination
Mol Ther. 2013 Oct;21(10):1862-75. doi: 10.1038/mt.2013.132. Epub 2013 Jun 25.

Dose-dependent neuroprotection of VEGF₁₆₅ in Huntington's disease striatum.

Author information

1
Division of Brain Sciences, Department of Gene Therapy, Faculty of Medicine, Centre for Neuroinflammation & Neurodegeneration, Imperial College London, Hammersmith Hospital Campus, London, UK.

Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by abnormal polyglutamine expansion in the huntingtin protein (Exp-Htt). Currently, there are no effective treatments for HD. We used bidirectional lentiviral transfer vectors to generate in vitro and in vivo models of HD and to test the therapeutic potential of vascular endothelial growth factor 165 (VEGF₁₆₅). Lentiviral-mediated expression of Exp-Htt caused cell death and aggregate formation in human neuroblastoma SH-SY5Y and rat primary striatal cultures. Lentiviral-mediated VEGF₁₆₅ expression was found to be neuroprotective in both of these models. Unilateral stereotaxic vector delivery of Exp-Htt vector in adult rat striatum led to progressive inclusion formation and striatal neuron loss at 10 weeks post-transduction. Coinjection of a lower dose VEGF₁₆₅ significantly attenuated DARPP-32(+) neuronal loss, enhanced NeuN staining and reduced Exp-Htt aggregation. A tenfold higher dose VEGF₁₆₅ led to overt neuronal toxicity marked by tissue damage, neovascularization, extensive astrogliosis, vascular leakage, chronic inflammation and distal neuronal loss. No overt behavioral phenotype was observed in these animals. Expression of VEGF₁₆₅ at this higher dose in the brain of wild-type rats led to early mortality with global neuronal loss. This report raises important safety concerns about unregulated VEGF₁₆₅ CNS applications.

PMID:
23799534
PMCID:
PMC4059596
DOI:
10.1038/mt.2013.132
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center