Anterograde Axonal Transport of AAV2-GDNF in Rat Basal Ganglia

Ciesielska, Agnieszka; Mittermeyer, Gabriele; Hadaczek, Piotr; Kells, Adrian P.; Forsayeth, John; Bankiewicz, Krystof S.

doi:10.1038/mt.2010.248

Cited by 67 publications

(75 citation statements)

References 38 publications

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“…We have previously reported that the AAV2-hAADC distribution appears to broaden slowly over time in NHP, resulting in a larger coverage of target regions (Daadi et al, 2006). In addition, because AAV2 vector is transported anterogradely through the axons (Ciesielska et al, 2011), we also found AADC expression in structures outside the striatum such as the globus pallidus, subthalamic nucleus, substantia nigra pars reticulata, and thalamus.…”

Section: Discussionmentioning

confidence: 53%

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Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

et al. 2012

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Degeneration of nigrostriatal neurons in Parkinson's disease (PD) causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa (l-DOPA) into dopamine in the striatum. Because loss of this enzyme appears to be a major driver of progressive impairment of response to the mainstay drug, l-DOPA, one promising approach has been to use gene therapy to restore AADC activity in the human putamen and thereby restore normal l-DOPA response in patients with PD. An open-label phase I clinical trial of this approach in patients with PD provided encouraging signs of improvement in Unified Parkinson's Disease Rating Scale scores and reductions in antiparkinsonian medications. However, such improvement was modest compared with the results previously reported in parkinsonian rhesus macaques. The reason for this discrepancy may have been that the relatively small volume of vector infused in the clinical study restricted the distribution of AADC expression, such that only about 20% of the postcommissural putamen was covered, as revealed by l-[3-18 F]-a-methyltyrosine-positron emission tomography. To achieve more quantitative distribution of vector, we have developed a visual guidance system for parenchymal infusion of AAV2. The purpose of the present study was to evaluate the combined magnetic resonance imaging-guided delivery system with AAV2-hAADC under conditions that approximate the intended clinical protocol. Our data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.

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Section: Discussionmentioning

confidence: 53%

“…2b). We noted some AADC expression in neuronal cell bodies and fibers in structures within the infused hemisphere, such as in the internal and external globus pallidus, subthalamic nucleus, and substantia nigra pars reticulata (data not shown), indicating anterograde transport of the vector (Ciesielska et al, 2011).…”

Section: Image-guided Aav2 Delivery 213mentioning

confidence: 99%

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

et al. 2012

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“…Earlier a dissociative expression of Ad lacZ gene transfection was found in ischemic rat brain [17]. It has been reported by others, too, that the transfection efficiency and transgene expression can be dependent on the lesion and tissue [19,20]. Therefore, it is likely that the transfection efficiency of gene vectors in the target cells and tissues would be affected by methodological parameters and physiological conditions.…”

Section: Resultsmentioning

confidence: 99%

Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

Raasmaja¹,

Lehtonen²,

Kääriäinen³

et al. 2013

OJGen

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The use of gene therapy has been intensively studied as a potential method to treat Parkinson's disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the outcome of gene delivery or on the physiological state of target tissues have not been analyzed as much and systematically. Therefore, we have infused adenovirus vectors expressing either a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into striatum in a rat model of PD. The experimental procedures were tested using the Ad lacZ vector in order to optimize concentrations, volumes, infusion speeds and transfection times. The expression of Ad lacZ vector was lower and declined earlier in the lesioned than unlesioned striatum suggesting that the lesion affects on the transfection efficiency and outcome of gene transfection. The effect of three different approaches of Ad TH vector transfection was compared: 1) the delivery of Ad TH gene vector alone into one single site of striatum, 2) the delivery of Ad TH gene vector alone into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into one site of striatum followed by a continuous infusion of tetrahydrobiopterin (BH4) cofactor with a mini pump. There was a small and transient unsignificant decrease in the turning behavior when the Ad TH vector was delivered into one site of the striatum. Simultaneous infusion into several sites or together with BH4 cofactor did not improve more the effect of gene delivery. Thus, although the effects were unsignificant, the Ad TH transfection seemed to decrease the turning behavior in the rat model of PD and the optimal effect was seen at some specific doses and time points. Furthermore, the outcome of gene therapy could depend in addition to the amount and efficacy of gene vectors also on the physiological state and experimental strategies.

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“…Numerous studies ( Jakobsson et al, 2003;Ciesielska et al, 2011;Richardson et al, 2011;Drinkut et al, 2012) have previously reported that striatal transgene expression targeted to neurons resulted in transgene products in the SNpc/pr, the globus pallidus, and the subthalamic nucleus, in both lesioned and unlesioned hemispheres. This was possibly because of retrograde delivery from striatal dopaminergic nerve terminals to the cell bodies in the SNpc (Tomac et al, 1995) and anterograde axonal transport from striatal neurons to the afferent regions via the indirect pathway, plus axonal sprouting between the two striatal hemispheres (Ciesielska et al, 2011;Richardson et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…This was possibly because of retrograde delivery from striatal dopaminergic nerve terminals to the cell bodies in the SNpc (Tomac et al, 1995) and anterograde axonal transport from striatal neurons to the afferent regions via the indirect pathway, plus axonal sprouting between the two striatal hemispheres (Ciesielska et al, 2011;Richardson et al, 2011). These off-target effects may provide some advantages in GDNF application for PD treatment, but levels of GDNF transported indirectly to these afferent regions are unpredictable, particularly when higher vector doses or longer expression times are required (Bartus et al, 2011;Drinkut et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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Standard integration-proficient lentiviral vectors (IPLVs) are effective at much lower doses than other vector systems and have shown promise for gene therapy of Parkinson's disease (PD). Their main drawback is the risk of insertional mutagenesis. The novel biosafety-enhanced integration-deficient lentiviral vectors (IDLVs) may offer a significant enhancement in biosafety, but have not been previously tested in a model of a major disease. We have assessed biosafety and transduction efficiency of IDLVs in a rat model of PD, using IPLVs as a reference. Genomic insertion of lentivectors injected into the lesioned striatum was studied by linear amplification-mediated polymerase chain reaction (PCR), followed by deep sequencing and insertion site analysis, demonstrating lack of significant IDLV integration. Reporter gene expression studies showed efficient, long-lived, and transcriptionally targeted expression from IDLVs injected ahead of lesioning in the rat striatum, although at somewhat lower expression levels than from IPLVs. Transgenic human glial cell line-derived neurotrophic factor (hGDNF) expression from IDLVs was used for a long-term investigation of lentivectormediated, transcriptionally targeted neuroprotection in this PD rat model. Vectors were injected before striatal lesioning, and the results showed improvements in nigral dopaminergic neuron survival and behavioral tests regardless of lentiviral integration proficiency, although they confirmed lower expression levels of hGDNF from IDLVs. These data demonstrate the effectiveness of IDLVs in a model of a major disease and indicate that these vectors could provide long-term PD treatment at low dose, combining efficacy and biosafety for targeted central nervous system applications.

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Anterograde Axonal Transport of AAV2-GDNF in Rat Basal Ganglia

Cited by 67 publications

References 38 publications

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

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

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