Dopamine Gene Therapy for Parkinson's Disease in a Nonhuman Primate Without Associated Dyskinesia

Article (PDF Available)inScience translational medicine 1(2):2ra4 · October 2009with260 Reads
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.


    • "The polyclonal pattern of LV integration, the preferential targeting of neural-specific genes without preferential insertions in genes involved in tumor formation or neurological disorders that we report here for the first time in NHP are in line with previous data obtained in rodents (Bartholomae et al, 2011; Lattanzi et al, 2014) and further point to a low genotoxic risk associated with the proposed GT platform. The CNS-restricted distribution of LV particles (Jarraya et al, 2009; Lattanzi et al, 2014) and, consequently, the absence of off-target LV integration in the periphery represent an additional favorable safety trait of this GT platform. According to previous studies performed in mice (brain volume % 0.5 cm 3 ) (Lattanzi et al, 2010Lattanzi et al, , 2014), we estimated that % 1 × 10 6 TU/cm 3 could be safe and potentially effective in achieving enzyme correction in the brain of juvenile NHP (brain volume % 60–65 cm 3 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLDor Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes inCNStissues ofMLDandGLDmice. Here, we investigated whether this strategy is similarly effective in juvenile non-human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normalNHPdelivering a clinically relevant lentiviral vector encoding for the humanARSAtransgene. Then, we injected a lentiviral vector coding for the humanGALCtransgene in Krabbe-affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviralGTin this uniqueLSDmodel. We showed favorable safety profile and consistent pattern ofLVtransduction and enzyme biodistribution in the two models, supporting the robustness of the proposedGTplatform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the wholeCNSand inCSF, leading to supraphysiologicalARSAactivity in normalNHPand close to physiologicalGALCactivity in the KrabbeNHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviralGTto addressCNSpathology inMLD, GLD, and other neurodegenerativeLSD.
    Full-text · Article · Mar 2016
    • "In the first group, the enzyme aromatic L-amino acid decarboxylase (AADC) is supplied surgically, by means of an adeno-associated viral (AAV2) vector, to striatal neurons; here it is able to convert L-dopa (still supplied exogenously by tablets) into the DA necessary for neuromodulation (Bankiewicz et al., 2006). In contrast, the Oxford group has used a multi-cistronic (lentiviral) vector that incorporates genes for three enzymes (guanosine triphosphate [GTP] cyclohydrolase 1 [GCH1], tyrosine hydroxylase [TH], and AADC—marketed as ProSavinV R , Oxford BioMedica, Oxford, UK), thereby supplying the entire molecular machinery for manufacturing DA (Azzouz et al., 2002; Jarraya et al., 2009). Both approaches have yielded encouraging results in early phase I studies, with the treatments being well tolerated over several years. "
    [Show abstract] [Hide abstract] ABSTRACT: The characteristic and selective degeneration of a unique population of cells – the nigrostriatal dopamine (DA) neurons – that occurs in Parkinson's disease (PD) has made the condition an iconic target for cell replacement therapies. Indeed transplantation of fetal ventral mesencephalic cells into the dopamine-deficient striatum was first trialled nearly 30 years ago, at a time when other treatments for the disease were less well developed. Over recent decades standard treatments for PD have advanced, and newer biological therapies are now emerging. In the 21st century, stem cell technology will have to compete alongside other sophisticated treatments, including deep brain stimulation and gene therapies. In this review we examine how stem cell based transplantation therapies compare with these novel and emerging treatments in the management of this common condition. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014
    • "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. "
    [Show abstract] [Hide abstract] 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.
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