title: Efficient Expression of Igf-1 from Lentiviral Vectors Protects In Vitro but Does Not Mediate Behavioral Recovery of a Parkinsonian Lesion in Rats.
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.
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London , Egham, United Kingdom.
authors.forename: Ngoc B
authors.initials: NB
authors.lastname: Lu-Nguyen
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London , Egham, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Broadstock
authors.affiliation: School of Biological Sciences, Royal Holloway, University of London , Egham, United Kingdom.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Yáñez-Muñoz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D009474:Neurons / Q000166:cytology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
chemical_list: D009414:Nerve Growth Factors; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D016627:Oxidopamine