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: 15.84). 10/2009; 1(2):2ra4. DOI: 10.1126/scitranslmed.3000130
Source: PubMed


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
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    • "Following publication of efficacy results in nonhuman primates with the trisictronic lenti-vector expressing three enzymes involved in dopamine production,11 an uncontrolled, open label, dose-escalation study was conducted in 15 PD subjects. Three ascending doses were tested, involving a 5-fold dose range. "
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    ABSTRACT: Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path towards regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing CNS gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection, and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward - beyond our past limits.Molecular Therapy (2013); doi:10.1038/mt.2013.281.
    Full-text · Article · Dec 2013 · Molecular Therapy
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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.
    Full-text · Article · Oct 2012 · Human Gene Therapy Methods
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    • "The key enzymes involved in dopamine metabolism are tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), and GTP-cyclohydrolase-1 (GCH-1). Animal studies using this approach have been promising and human phase I/II trials of a lentiviral vector containing genes encoding all three key enzymes (ProSavin), are ongoing [14, 54, 55]. The second approach aims to modulate basal ganglia circuitry affected by PD, for example, by increasing levels of GABA to counteract the overactivity of the subthalamic nucleus observed in this condition. "
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    ABSTRACT: Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.
    Full-text · Article · Mar 2012
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