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Dopamine gene therapy for Parkinson’s disease in a nonhuman primate without associated dyskinesia

Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France.
Science translational medicine (Impact Factor: 14.41). 10/2009; 1(2):2ra4. DOI: 10.1126/scitranslmed.3000130
Source: PubMed

ABSTRACT In Parkinson's disease, degeneration of specific neurons in the midbrain can cause severe motor deficits, including tremors and the inability to initiate movement. The standard treatment is administration of pharmacological agents that transiently increase concentrations of brain dopamine and thereby discontinuously modulate neuronal activity in the striatum, the primary target of dopaminergic neurons. The resulting intermittent dopamine alleviates parkinsonian symptoms but is also thought to cause abnormal involuntary movements, called dyskinesias. To investigate gene therapy for Parkinson's disease, we simulated the disease in macaque monkeys by treating them with the complex I mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which induces selective degeneration of dopamine-producing neurons. In this model, we demonstrated that injection of a tricistronic lentiviral vector encoding the critical genes for dopamine synthesis (tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and guanosine 5'-triphosphate cyclohydrolase 1) into the striatum safely restored extracellular concentrations of dopamine and corrected the motor deficits for 12 months without associated dyskinesias. Gene therapy-mediated dopamine replacement may be able to correct Parkinsonism in patients without the complications of dyskinesias.

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Available from: Philippe Hantraye, Jul 28, 2015
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    • "T he development of lentiviral gene therapy vectors to treat genetic disorders in humans is becoming more widespread, with several such therapeutics currently proceeding through clinical trials in Europe and North America (DiGiusto et al., 2010; Galy and Thrasher, 2010; Sadelain et al., 2010; Porter et al., 2011; Campochiaro, 2012; Cartier et al., 2012). We have developed a highly engineered nonprimate lentiviral vector system based on equine infectious anemia virus (EIAV) that has an excellent safety profile in preclinical trials ( Jarraya et al., 2009; and K.A. Mitrophanous, unpublished ). Indeed, early in 2008 the first in vivo administration of a lentiviral vector in humans was performed with a vector based on EIAV (ProSavin Ò ). "
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    ABSTRACT: The release of lentiviral vectors for clinical use requires the testing of vector material, production cells and, if applicable, ex vivo transduced cells for the presence of replication-competent lentivirus (RCL). Vectors derived from the non-primate lentivirus equine infectious anaemia virus (EIAV) have been directly administered to patients in several clinical trials, with no toxicity observed to date. Since EIAV does not replicate in human cells, and that putative RCLs derived from vector components within the human production cells would most likely be human cell-tropic, we previously developed an RCL assay utilising amphotropic murine leukaemia virus (MLV) as a surrogate positive control and human cells as RCL amplification/indicator cells. Here we report an additional RCL assay that tests for the presence of theoretical 'equine-tropic' RCLs. This approach provides further assurance of safety by detecting putative RCLs with an equine cell-specific tropism that might not be efficiently amplified by the human cell based RCL assay. We tested the ability of accessory gene deficient EIAV mutant viruses to replicate in a highly permissive equine cell line to direct our choice of a suitable EIAV-derived positive control. In addition, we report for the first time the mathematical rationale for use of Poisson distribution to calculate minimal infectious dose of positive control virus and for use in monitoring assay positive/spike control failures in accumulating data sets. No RCLs have been detected in Good Manufacturing Practice (GMP)-compliant RCL assays to date, further demonstrating that RCL formation is highly unlikely in contemporary minimal lentiviral vector systems.
    Human Gene Therapy Methods 10/2012; DOI:10.1089/hum.2012.102 · 1.64 Impact Factor
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    • "Subsequent in vivo microdialysis measurement in the MPTP macaque model demonstrated a greater increase in extracellular levels, so the therapeutic efficacy may have been greater than first thought (Jarraya 2009). Treated macaques exhibited restoration of the firing rate and pattern of neurons within the basal ganglia and reduced metabolic activity within the subthalamic nucleus, coupled with functional improvements. "
    Towards New Therapies for Parkinson's Disease, 11/2011; , ISBN: 978-953-307-463-4
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    • "Furthermore, several animal models of PD are available to test new therapies. Actually, promising preclinical gene therapy studies focusing on the correction of dopamine deficiency are currently in progress (Azzouz et al., 2002;Jarraya et al., 2009). However, a limitation with this level of analysis is that it sidesteps the main goal that a current therapeutical approach for PD should afford: to block and/or counteract dopamine neuron derangement. "
    Etiology and Pathophysiology of Parkinson's Disease, 10/2011; , ISBN: 978-953-307-462-7
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