Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

Wang, L; Muramatsu, Shin‐ichi; Lü, Yanyan; Ikeguchi, Kunihiko; Fujimoto, Ken’ichi; Okada, Takashi; Mizukami, Hiroaki; Hanazono, Yutaka; Kume, Akihiro; Urano, Fumihiro; Ichinose, Hiroshi; Nagatsu, Toshiharu; Nakano, Imaharu; Ozawa, Keiya

doi:10.1038/sj.gt.3301682

Cited by 168 publications

(88 citation statements)

References 41 publications

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“…Alternatively, as a recent report showed that delivery of recombinant GDNF directly into the putamen of five Parkinson's disease patients in a phase I safety trial produced functional improvement, 25 gene transfer might allow long-term production of neuroprotective growth factors, thus resulting in a better outcome. 26 Indeed, gene therapy for Parkinson's disease in animal models also induced functional recovery using an AAV vector 27 or lentiviral vector, 28 although these vectors have several major problems such as immunogenicity. These diseases might be targeted using the microbubble-enhanced ultrasound method, as naked plasmid DNA is much safer and easier to handle.…”

Section: Discussionmentioning

confidence: 99%

Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound

et al. 2004

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“…In fact, various factors including GDNF and VEGF have been shown to increase dopaminergic neuronal survival and promote survival and axonal growth in animal models of PD. [9][10][11] In addition to those factors, we and others have reported a potential therapeutic strategy using hepatocyte growth factor (HGF). [12][13][14][15][16][17][18][19] HGF acts as a neurotrophic and survival factor for embryonic motor neurons.…”

Section: Introductionmentioning

confidence: 99%

Prevention of onset of Parkinson’s disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson’s disease

et al. 2006

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.

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“…To date, most gene therapeutic approaches to PD have involved AAV-mediated transgene delivery to the striatum, the target projection area of nigral dopaminergic neurons. Indeed, the striatum has been the prime site for vector delivery in PD therapies aiming at dopamine restoration through expression of dopamine-synthesizing enzymes in striatal neurons (During et al, 1998;Wang et al, 2002;Eberling et al, 2008;Christine et al, 2009;Jarraya et al, 2009;Muramatsu et al, 2010;Valles et al, 2010), and also in gene therapeutic approaches involving neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) or neurturin (Kordower et al, 2000;Eslamboli et al, 2005;Eberling et al, 2009;Marks et al, 2010). The protective effect of neurotrophic factors released by transduced striatal neurons relies on their uptake by dopaminergic fibers in the striatum and retrograde axonal transport to the cell soma in the SNpc.…”

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confidence: 99%

Direct and Retrograde Transduction of Nigral Neurons with AAV6, 8, and 9 and Intraneuronal Persistence of Viral Particles

Löw

Aebischer²,

Schneider³

2013

Human Gene Therapy

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Recombinant adeno-associated viral (AAV) vectors of serotypes 6, 8, and 9 were characterized as tools for gene delivery to dopaminergic neurons in the substantia nigra for future gene therapeutic applications in Parkinson's disease. While vectors of all three serotypes transduced nigral dopaminergic neurons with equal efficiency when directly injected to the substantia nigra, AAV6 was clearly superior to AAV8 and AAV9 for retrograde transduction of nigral neurons after striatal delivery. For sequential transduction of nigral dopaminergic neurons, the combination of AAV9 with AAV6 proved to be more powerful than AAV8 with AAV6 or repeated AAV6 administration. Surprisingly, single-stranded viral genomes persisted in nigral dopaminergic neurons within cell bodies and axon terminals in the striatum, and intact assembled AAV capsid was enriched in nuclei of nigral neurons, 4 weeks after virus injections to the substantia nigra. 6-Hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra reduced the number of viral genomes in the striatum, in line with viral genome persistence in axon terminals. However, 6-OHDA-induced axonal degeneration did not induce any transsynaptic spread of AAV infection in the striatum. Therefore, the potential presence of viral particles in axons may not represent an important safety issue for AAV gene therapy applications in neurodegenerative diseases.

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Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

Cited by 168 publications

References 41 publications

Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound

Development of efficient plasmid DNA transfer into adult rat central nervous system using microbubble-enhanced ultrasound

Prevention of onset of Parkinson’s disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson’s disease

Direct and Retrograde Transduction of Nigral Neurons with AAV6, 8, and 9 and Intraneuronal Persistence of Viral Particles

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