| 1. |
- Grealish, Shane, et al.
(författare)
-
Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson's Disease.
- 2014
-
Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 15:5, s. 653-665
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Tidskriftsartikel (refereegranskat)abstract
- Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson's disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson's disease.
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| 2. |
- Kirik, Deniz, et al.
(författare)
-
Imaging in cell-based therapy for neurodegenerative diseases.
- 2005
-
Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 32:Suppl 2, s. 417-434
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Forskningsöversikt (refereegranskat)abstract
- Fetal cell transplantation for the treatment of Parkinsonrsquos and Huntingtonrsquos diseases has been developed over the past two decades and is now in early clinical testing phase. Direct assessment of the graftrsquos survival, integration into the host brain and impact on neuronal functions requires advanced in vivo neuroimaging techniques. Owing to its high sensitivity, positron emission tomography is today the most widely used tool to evaluate the viability and function of the transplanted tissue in the brain. Nuclear magnetic resonance techniques are opening new possibilities for imaging neurochemical events in the brain. The ultimate goal will be to use the combination of multiple imaging modalities for complete functional monitoring of the repair processes in the central nervous system.
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| 3. |
- Leriche, Ludovic, et al.
(författare)
-
Positron Emission Tomography Imaging Demonstrates Correlation between Behavioral Recovery and Correction of Dopamine Neurotransmission after Gene Therapy
- 2009
-
Ingår i: The Journal of Neuroscience. - 1529-2401. ; 29:5, s. 1544-1553
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Tidskriftsartikel (refereegranskat)abstract
- In vivo gene transfer using viral vectors is an emerging therapy for neurodegenerative diseases with a clinical impact recently demonstrated in Parkinson's disease patients. Recombinant adeno-associated viral (rAAV) vectors, in particular, provide an excellent tool for long-term expression of therapeutic genes in the brain. Here we used the [C-11] raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-2-hydroxy6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) andGTPcyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [C-11] raclopride binding in hemiparkinsonian rats. Importantly, we show in vivo by microPET imaging and postmortem by classical binding assays performed in the very same animals that the changes in [C-11] raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D-2 receptors, providing evidence for reconstitution of a functional pool of endogenous dopamine in the striatum. Moreover, the extent of the normalization in this non-invasive imaging measure was highly correlated with the functional recovery in motor behavior. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as an in vivo imaging technique to follow TH + GCH1 gene therapy in PD patientsandprovideanadditionalobjectivemeasuretoapotentialclinicaltrialu singrAAVvectorstodeliverL-3,4-dihydroxyphenylanalineinthebrain.
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| 4. |
- Lundberg, Cecilia, et al.
(författare)
-
Applications of lentiviral vectors for biology and gene therapy of neurological disorders.
- 2008
-
Ingår i: Current Gene Therapy. - 1566-5232. ; 8:6, s. 461-473
-
Tidskriftsartikel (refereegranskat)abstract
- Recombinant lentiviral vectors (rLV) are powerful tools for gene transfer to the central nervous system (CNS) and hold great potential as a therapeutic gene therapy strategy for neurological disorders. Recent data indicate that rLVs are suitable for functional studies in the CNS by over expression or knock down of specific proteins. Based on a variety of lentiviruses species, different vector systems have been developed. However, the most commonly used rLV vector is based on the human immunodeficiency virus 1 (HIV-1). Here we describe the use of such vectors to achieve cell-specific transgene expression in the brain. In this setting, rLVs are versatile tools both due to their relatively large cloning capacity and their ability to transduce non-dividing cells. Furthermore, we discuss the preclinical development of gene therapy based on enzyme replacement and/or delivery of neurotrophic factors for neurodegenerative diseases and CNS manifestations of lysosomal storage diseases. Neuroprotective strategies that aim to deliver glial cell line-derived neurotrophic factor and ciliary neurotrophic factor for Parkinson's and Huntington's diseases in particular have been documented with success in appropriate animal models. More recently, rLVs were shown to be suitable to express small interfering RNA for treatment in models of Alzheimer's disease and amyotrophic lateral sclerosis. Finally, we present a review of the use of rLVs to model neurodegenerative diseases. rLVs have proven to be a very versatile tool to create genetic models of both Parkinson's and Huntington's diseases and thus provide possibilities to study complex genetic interactions in otherwise wild-type animals evading the necessity to create transgenic mice. Moreover, the potential of these vectors in the development of gene therapy to treat neurological disorders is considerable, which is supported by the fact that clinical trials using rLVs are underway.
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| 5. |
- Sahin, Gurdal, et al.
(författare)
-
Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease.
- 2014
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:3
-
Tidskriftsartikel (refereegranskat)abstract
- Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.
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