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.
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References
1.
ChenQ, HeY, and YangK. Gene therapy for Parkinson's disease: progress and challenges. Curr Gene Ther, 2005; 5:71–80.
2.
GillSS, PatelNK, HottonGR, et al.Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med, 2003; 9:589–595.
3.
MarksWJJr., OstremJL, VerhagenL, et al.Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol, 2008; 7:400–408.
4.
SunM, KongL, WangX, et al.Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease. Brain Res, 2005; 1052:119–129.
5.
LindholmP, VoutilainenMH, LaurenJ, et al.Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature, 2007; 448:73–77.
6.
VoutilainenMH, BackS, PorstiE, et al.Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease. J Neurosci, 2009; 29:9651–9659.
7.
LangAE, GillS, PatelNK, et al.Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol, 2006; 59:459–466.
8.
KnuselB, MichelPP, SchwaberJS, et al.Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J Neurosci, 1990; 10:558–570.
9.
DuanC, and XuQ. Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions. Gen Comp Endocrinol, 2005; 142:44–52.
10.
FernandezS, FernandezAM, Lopez-LopezC, et al.Emerging roles of insulin-like growth factor-I in the adult brain. Growth Horm IGF Res, 2007; 17:89–95.
11.
RussoVC, GluckmanPD, FeldmanEL, et al.The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev, 2005; 26:916–943.
12.
FernandezAM, and Torres-AlemanI. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci, 2012; 13:225–239.
13.
Avila-GomezIC, Velez-PardoC, and Jimenez-Del-RioM. Effects of insulin-like growth factor-1 on rotenone-induced apoptosis in human lymphocyte cells. Basic Clin Pharmacol Toxicol, 2010; 106:53–61.
14.
SunX, HuangL, ZhangM, et al.Insulin like growth factor-1 prevents 1-methyl-4-phenylphyridinium-induced apoptosis in PC12 cells through activation of glycogen synthase kinase-3β. Toxicology, 2010; 271:5–12.
15.
WangL, YangHJ, XiaYY, et al.Insulin-like growth factor 1 protects human neuroblastoma cells SH-EP1 against MPP+-induced apoptosis by AKT/GSK-3β/JNK signaling. Apoptosis, 2010; 15:1470–1479.
16.
LandiF, CapoluongoE, RussoA, et al.Free insulin-like growth factor-I and cognitive function in older persons living in community. Growth Horm IGF Res, 2007; 17:58–66.
17.
TongM, DongM, and de la MonteSM. Brain insulin-like growth factor and neurotrophin resistance in Parkinson's disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J Alzheimers Dis, 2009; 16:585–599.
18.
GuanJ, KrishnamurthiR, WaldvogelHJ, et al.N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. Brain Res, 2000; 859:286–292.
19.
OffenD, ShtaifB, HadadD, et al.Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson's disease. Neurosci Lett, 2001; 316:129–132.
20.
QuesadaA, LeeBY, and MicevychPE. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease. Dev Neurobiol, 2008; 68:632–644.
21.
QuesadaA, and MicevychPE. Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions. J Neurosci Res, 2004; 75:107–116.
22.
SalvatoreMF, AiY, FischerB, et al.Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol, 2006; 202:497–505.
23.
DowdE, MonvilleC, TorresEM, et al.Lentivector-mediated delivery of GDNF protects complex motor functions relevant to human Parkinsonism in a rat lesion model. Eur J Neurosci, 2005; 22:2587–2595.
24.
EmborgME, MoiranoJ, RaschkeJ, et al.Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF. Neurobiol Dis, 2009; 36:303–311.
25.
GeorgievskaB, KirikD, and BjorklundA. Overexpression of glial cell line-derived neurotrophic factor using a lentiviral vector induces time- and dose-dependent downregulation of tyrosine hydroxylase in the intact nigrostriatal dopamine system. J Neurosci, 2004; 24:6437–6445.
26.
KordowerJH, EmborgME, BlochJ, et al.Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science, 2000; 290:767–773.
27.
PalfiS, LeventhalL, ChuY, et al.Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J Neurosci, 2002; 22:4942–4954.
28.
Yáñez-MuñozRJ, BalagganKS, MacNeilA, et al.Effective gene therapy with nonintegrating lentiviral vectors. Nat Med, 2006; 12:348–353.
29.
WanischK, and Yáñez-MuñozRJ. Integration-deficient lentiviral vectors: a slow coming of age. Mol Ther, 2009; 17:1316–1332.
30.
Lu-NguyenNB, BroadstockM, SchliesserMG, et al.Transgenic expression of human glial cell line-derived neurotrophic factor from integration-deficient lentiviral vectors is neuroprotective in a rodent model of Parkinson's disease. Hum Gene Ther, 2014; 25:631–641.
31.
HiokiH, KamedaH, NakamuraH, et al.Efficient gene transduction of neurons by lentivirus with enhanced neuron-specific promoters. Gene Ther, 2007; 14:872–882.
32.
JakobssonJ, EricsonC, JanssonM, et al.Targeted transgene expression in rat brain using lentiviral vectors. J Neurosci Res, 2003; 73:876–885.
33.
LiM, HusicN, LinY, et al.Optimal promoter usage for lentiviral vector-mediated transduction of cultured central nervous system cells. J Neurosci Methods, 2010; 189:56–64.
34.
MashayekhiF, MirzajaniE, NajiM, et al.Expression of insulin-like growth factor-1 and insulin-like growth factor binding proteins in the serum and cerebrospinal fluid of patients with Parkinson's disease. J Clin Neurosci, 2010; 17:623–627.
35.
PruszakJ, JustL, IsacsonOet al., Isolation and culture of ventral mesencephalic precursor cells and dopaminergic neurons from rodent brains. Curr Protoc Stem Cell Biol 2009;Chapter 2:Unit 2D.5.
36.
TakeshimaT, ShimodaK, SauveY, et al.Astrocyte-dependent and -independent phases of the development and survival of rat embryonic day 14 mesencephalic, dopaminergic neurons in culture. Neuroscience, 1994; 60:809–823.
37.
BoulosS, MeloniBP, ArthurPG, et al.Assessment of CMV, RSV and SYN1 promoters and the woodchuck post-transcriptional regulatory element in adenovirus vectors for transgene expression in cortical neuronal cultures. Brain Res, 2006; 1102:27–38.
38.
PaxinosG, and WatsonC. The Rat Brain in Stereotaxic Coordinates, 6th ed. Elsevier/Academic Press, New York. 2007.
39.
BartusRT, HerzogCD, BishopK, et al.Issues regarding gene therapy products for Parkinson's disease: the development of CERE-120 (AAV-NTN) as one reference point. Parkinsonism Relat Disord, 2007; 13Suppl 3:S469–S477.
40.
ChaudhuriKR, HealyDG, and SchapiraAH. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol, 2006; 5:235–245.
41.
LindgrenHS, and DunnettSB. Cognitive dysfunction and depression in Parkinson's disease: what can be learned from rodent models?. Eur J Neurosci, 2012; 35:1894–1907.
42.
HodgeRD, D'ErcoleAJ, and O'KuskyJR. Insulin-like growth factor-I (IGF-I) inhibits neuronal apoptosis in the developing cerebral cortex in vivo. Int J Dev Neurosci, 2007; 25:233–241.
43.
Mairet-CoelloG, TuryA, and DiCicco-BloomE. Insulin-like growth factor-1 promotes G1/S cell cycle progression through bidirectional regulation of cyclins and cyclin-dependent kinase inhibitors via the phosphatidylinositol 3-kinase/Akt pathway in developing rat cerebral cortex. J Neurosci, 2009; 29:775–788.
44.
DrinkutA, TereshchenkoY, SchulzJB, et al.Efficient gene therapy for Parkinson's disease using astrocytes as hosts for localized neurotrophic factor delivery. Mol Ther, 2012; 20:534–543.
45.
RichardsonRM, KellsAP, RosenbluthKH, et al.Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease. Mol Ther, 2011; 19:1048–1057.
46.
DesplatsP, LeeHJ, BaeEJ, et al.Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc Natl Acad Sci U S A, 2009; 106:13010–13015.
47.
ManfredssonFP, TumerN, ErdosB, et al.Nigrostriatal rAAV-mediated GDNF overexpression induces robust weight loss in a rat model of age-related obesity. Mol Ther, 2009; 17:980–991.
48.
ZawadaWM, KirschmanDL, CohenJJ, et al.Growth factors rescue embryonic dopamine neurons from programmed cell death. Exp Neurol, 1996; 140:60–67.
49.
EbertAD, BeresAJ, BarberAE, et al.Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease. Exp Neurol, 2008; 209:213–223.
50.
RedmondDEJr., BjugstadKB, TengYD, et al.Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A, 2007; 104:12175–12180.
51.
SadanO, ShemeshN, CohenY, et al.Adult neurotrophic factor-secreting stem cells: a potential novel therapy for neurodegenerative diseases. Isr Med Assoc J, 2009; 11:201–204.
52.
LinLF, DohertyDH, LileJD, et al.GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science, 1993; 260:1130–1132.
53.
CohickWS, and ClemmonsDR. The insulin-like growth factors. Annu Rev Physiol, 1993; 55:131–153.
54.
GranholmAC, ReylandM, AlbeckD, et al.Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons. J Neurosci, 2000; 20:3182–3190.
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