Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease

Tereshchenko, Julia; Maddalena, Andrea; Bähr, Mathias; Kügler, Sebastian

doi:10.1016/j.nbd.2014.01.009

Cited by 52 publications

(67 citation statements)

References 37 publications

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“…While a large number of neuroprotection studies (Bilang-Bleuel et al, 1997; Choi-Lundberg et al, 1997; Mandel et al, 1999; Bensadoun et al, 2000; Kirik et al, 2000; Kordower et al, 2000; Eslamboli et al, 2005; Bartus et al, 2011) have been published, only few works aimed at evaluating a potential neurorestorative effect (Kozlowski et al, 2000; Yang et al, 2009; Tereshchenko et al, 2014). In addition, the latter paradigm can refer to different approaches.…”

Section: Glial Cell Line-derived Neurotrophic Factor Gene Delivery: Pmentioning

confidence: 99%

“…Similarly, in other studies, neuroprotective effects in the absence of TH downregulation have been obtained by applying low GDNF doses either by injecting a low amount of viral vector (Eslamboli et al, 2005) or by controlling the level of transgene expression (Barroso-Chinea et al, 2016; Chtarto et al, 2016). Interestingly, using a discontinuous GDNF delivery paradigm in the partial rat 6-OHDA model, also allowed to reduce the behavioral symptoms as well as to maintain VMAT2-positive cells and innervation in the absence of TH downregulation (Tereshchenko et al, 2014). …”

Section: Glial Cell Line-derived Neurotrophic Factor Gene Delivery: Pmentioning

confidence: 99%

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Glial Cell Line-Derived Neurotrophic Factor Gene Delivery in Parkinson's Disease: A Delicate Balance between Neuroprotection, Trophic Effects, and Unwanted Compensatory Mechanisms

Tenenbaum

Humbert-Claude

2017

Front. Neuroanat.

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Glial cell line-derived neurotrophic factor (GDNF) and Neurturin (NRTN) bind to a receptor complex consisting of a member of the GDNF family receptor (GFR)-α and the Ret tyrosine kinase. Both factors were shown to protect nigro-striatal dopaminergic neurons and reduce motor symptoms when applied terminally in toxin-induced Parkinson's disease (PD) models. However, clinical trials based on intraputaminal GDNF protein administration or recombinant adeno-associated virus (rAAV)-mediated NRTN gene delivery have been disappointing. In this review, several factors that could have limited the clinical benefits are discussed. Retrograde transport of GDNF/NRTN to the dopaminergic neurons soma is thought to be necessary for NRTN/GFR-α/Ret signaling mediating the pro-survival effect. Therefore, the feasibility of treating advanced patients with neurotrophic factors is questioned by recent data showing that: (i) tyrosine hydroxylase-positive putaminal innervation has almost completely disappeared at 5 years post-diagnosis and (ii) in patients enrolled in the rAAV-NRTN trial more than 5 years post-diagnosis, NRTN was almost not transported to the substantia nigra pars compacta. In addition to its anti-apoptotic and neurotrophic properties, GDNF also interferes with dopamine homeostasis via time and dose-dependent effects such as: stimulation of dopamine neuron excitability, inhibition of dopamine transporter activity, tyrosine hydroxylase phosphorylation, and inhibition of tyrosine hydroxylase transcription. Depending on the delivery parameters, the net result of this intricate network of regulations could be either beneficial or deleterious. In conclusion, further unraveling of the mechanism of action of GDNF gene delivery in relevant animal models is still needed to optimize the clinical benefits of this new therapeutic approach. Recent developments in the design of regulated viral vectors will allow to finely adjust the GDNF dose and period of administration. Finally, new clinical studies in less advanced patients are warranted to evaluate the potential of AAV-mediated neurotrophic factors gene delivery in PD. These will be facilitated by the demonstration of the safety of rAAV administration into the human brain.

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Section: Glial Cell Line-derived Neurotrophic Factor Gene Delivery: Pmentioning

confidence: 99%

Section: Glial Cell Line-derived Neurotrophic Factor Gene Delivery: Pmentioning

confidence: 99%

Glial Cell Line-Derived Neurotrophic Factor Gene Delivery in Parkinson's Disease: A Delicate Balance between Neuroprotection, Trophic Effects, and Unwanted Compensatory Mechanisms

Tenenbaum

Humbert-Claude

2017

Front. Neuroanat.

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“…Activation of the receptor complex in neurons can lead to modification of various signaling events, including p38 MAPK, ERK, protein kinase B (AKT), and PKA (2,22,54). GDNF has been intensively studied as a potential therapeutic agent for neurodegenerative diseases, such as Parkinson's disease (37,55,64,66). In models of neurodegenerative diseases GDNF has positive effects on proliferation of neurons and is necessary for the maintenance of neuronal morphology (7).…”

Section: Gdnf Directly Promotes Barrier Maturation and Proliferation mentioning

confidence: 99%

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

Meir

Flemming

Burkard

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Regulation of the intestinal epithelial barrier is a differentiated process, which is profoundly deranged in inflammatory bowel diseases. Recent data provide evidence that the glial cell line-derived neurotrophic factor (GDNF) is critically involved in intestinal epithelial wound healing and barrier maturation and exerts antiapoptotic effects under certain conditions. Furthermore, not only the enteric nervous system, but also enterocytes synthesize GDNF in significant amounts, which points to a potential para- or autocrine signaling loop between enterocytes. Apart from direct effects of GDNF on enterocytes, an immunomodulatory role of this protein has been previously assumed because of a significant reduction of inflammation in a model of chronic inflammatory bowel disease after application of GDNF. In this review we summarize the current knowledge of GDNF on intestinal epithelial barrier regulation and discuss the novel role for GDNF as a regulator of intestinal barrier functions in health and disease.

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“…The basal transgene expression in this system in non-induced state is low, whereas after the activation by doxycycline the expression levels are comparable or higher than obtained using the CMV promoter 96, 97 . A similar system utilizing mifepristone, an approved small molecule drug, has recently been described 98 ; optimizing AAV serotype and timing of GDNF transgene expression resulted in efficient neuroprotection in rat 6-OHDA PD model 99 . The other approach is to use a dihydrofolate reductase-derived destabilizing domain (DD) fused to the transgene that leads to rapid degradation of the entire fusion protein; the DD is stabilized by blood-brain barrier penetrating small molecule ligand trimetoprim allowing for controlled transgene expression 100 .…”

Section: Viral Vectorsmentioning

confidence: 99%

Prospects of Neurotrophic Factors for Parkinson's Disease: Comparison of Protein and Gene Therapy

2015

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Neurotrophic factors (NTFs) hold great potential as therapeutic agents in the treatment of neurodegenerative conditions, including Parkinson's disease (PD), in which the progressive loss of dopamine neurons in the substantia nigra pars compacta causes severe motor symptoms. There is extensive evidence that in preclinical animal models of PD NTFs are both neuroprotective and neurorestorative. In particular, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), cerebral dopamine neurotrophic factor, and mesencephalic astrocyte-derived neurotrophic factor have shown great potential to restore dopamine neurocircuitry. Although some previous clinical trials have demonstrated limited efficacy of GDNF and NRTN, there are several concerns raised with these studies. Moreover, open-label studies with GDNF as well as a study with NRTN showed clinical improvement, particularly in patients with early-stage PD. Indeed, as previous clinical trials with NTFs were associated with several technical problems, there is a great need for further investigations. In this review we discuss the emerging and existing possibilities to use NTFs as neurorestorative agents and the ways to improve their efficacy, and compare gene therapy and recombinant protein therapy approaches for restoring the dopamine circuitry in PD.

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Pharmacologically controlled, discontinuous GDNF gene therapy restores motor function in a rat model of Parkinson's disease

Cited by 52 publications

References 37 publications

Glial Cell Line-Derived Neurotrophic Factor Gene Delivery in Parkinson's Disease: A Delicate Balance between Neuroprotection, Trophic Effects, and Unwanted Compensatory Mechanisms

Glial Cell Line-Derived Neurotrophic Factor Gene Delivery in Parkinson's Disease: A Delicate Balance between Neuroprotection, Trophic Effects, and Unwanted Compensatory Mechanisms

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

Prospects of Neurotrophic Factors for Parkinson's Disease: Comparison of Protein and Gene Therapy

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