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Hum Gene Ther. 2015 Nov;26(11):719-33. doi: 10.1089/hum.2015.016. Epub 2015 Oct 1.

Efficient Expression of Igf-1 from Lentiviral Vectors Protects In Vitro but Does Not Mediate Behavioral Recovery of a Parkinsonian Lesion in Rats.

Author information

1
School of Biological Sciences, Royal Holloway, University of London , Egham, United Kingdom.

Abstract

Gene therapy approaches delivering neurotrophic factors have offered promising results in both preclinical and clinical trials of Parkinson's disease (PD). However, failure of glial cell line-derived neurotrophic factor in phase 2 clinical trials has sparked a search for other trophic factors that may retain efficacy in the clinic. Direct protein injections of one such factor, insulin-like growth factor (IGF)-1, in a rodent model of PD has demonstrated impressive protection of dopaminergic neurons against 6-hydroxydopamine (6-OHDA) toxicity. However, protein infusion is associated with surgical risks, pump failure, and significant costs. We therefore used lentiviral vectors to deliver Igf-1, with a particular focus on the novel integration-deficient lentiviral vectors (IDLVs). A neuron-specific promoter, from the human synapsin 1 gene, excellent for gene expression from IDLVs, was additionally used to enhance Igf-1 expression. An investigation of neurotrophic effects on primary rat neuronal cultures demonstrated that neurons transduced with IDLV-Igf-1 vectors had complete protection on withdrawal of exogenous trophic support. Striatal transduction of such vectors into 6-OHDA-lesioned rats, however, provided neither protection of dopaminergic substantia nigra neurons nor improvement of animal behavior.

PMID:
26222254
PMCID:
PMC4651049
DOI:
10.1089/hum.2015.016
[Indexed for MEDLINE]
Free PMC Article

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