Viral Vector-Based Models of Parkinson’s Disease

2014 ◽  
pp. 271-301 ◽  
Author(s):  
Anke Van der Perren ◽  
Chris Van den Haute ◽  
Veerle Baekelandt
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Vector

scholarly journals Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease

2020 ◽  
Vol 91 (11) ◽  
pp. 1210-1218 ◽  
Author(s):  
R Mark Richardson ◽  
Krystof S Bankiewicz ◽  
Chadwick W Christine ◽  
Amber D Van Laar ◽  
Robert E Gross ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Viral Vector ◽  
Data Driven ◽  
Surgical Approaches ◽  
Acid Decarboxylase ◽  
Projection Neurons ◽  
Virus Serotype ◽  
Vector Delivery

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

Viral Vector Mediated Overexpression of Human α-Synuclein in the Nigrostriatal Dopaminergic Neurons: A New Model for Parkinson's Disease

CNS Spectrums ◽  
2005 ◽  
Vol 10 (3) ◽  
pp. 235-244 ◽  
Author(s):  
Matthew Maingay ◽  
Marina Romero-Ramos ◽  
Deniz Kirik
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Vectors ◽  
Viral Vector ◽  
Disease Process ◽  
Deficiency Syndrome ◽  
Toxic Substances ◽  
Testing Strategies ◽  
Ventral Mesencephalic ◽  
The Brain

AbstractParkinson's disease is predominantly a dopamine deficiency syndrome, which is produced in the brain by the loss of cells located in a small area in the ventral midbrain called the substantia nigra. Complete unilateral dopamine lesions, based on the administration of toxic substances (ie, 6-hydroxy-dopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates) have been extremely useful in testing strategies of replacement. For example, the functional and biochemical impact of the transplanted ventral mesencephalic dopaminergic progenitors has been characterized to a large extent, using the complete lesion model in rats. Over the last decade, however, studies addressing the ability of neurotrophic factors to protect injured dopamine cells prompted researchers to make available partial and progressive lesion models to allow a window of opportunity to interfere the disease progression. Recent findings relating a-synuclein with Parkinson's disease pathology have opened new possibilities to develop alternative models based on the overexpression of this protein using recombinant adeno-associated viral vectors, which is valuable not only for helping to better understand its involvement in the disease process, but also to more closely resemble the neurodegeneration found in Parkinson's disease.

scholarly journals α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

2021 ◽  
Author(s):  
Leo R Quinlan ◽  
Jara Maria Baena-Montes ◽  
Sahar Avazzadeh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Modeling ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Model Systems ◽  
The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

Gene Therapy in the Management of Parkinson’s Disease: Potential of GDNF as a Promising Therapeutic Strategy

2020 ◽  
Vol 20 (3) ◽  
pp. 207-222
Author(s):  
Tapan Behl ◽  
Ishnoor Kaur ◽  
Arun Kumar ◽  
Vineet Mehta ◽  
Gokhan Zengin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Dopamine Synthesis ◽  
Motor Symptoms ◽  
Ligand Complex

: The limitations of conventional treatment therapies in Parkinson’s disorder, a common neurodegenerative disorder, lead to the development of an alternative gene therapy approach. Multiple treatment options targeting dopaminergic neuronal regeneration, production of enzymes linked with dopamine synthesis, subthalamic nucleus neurons, regulation of astrocytes and microglial cells and potentiating neurotrophic factors, were established. Viral vector-based dopamine delivery, prodrug approaches, fetal ventral mesencephalon tissue transplantation and dopamine synthesizing enzyme encoding gene delivery are significant therapies evidently supported by numerous trials. The review primarily elaborates on the significant role of glial cell-line derived neurotrophic factor in alleviating motor symptoms and the loss of dopaminergic neurons in Parkinson’s disease. Neuroprotective and neuroregenerative effects of GDNF were established via preclinical and clinical study outcomes. The binding of GDNF family ligands with associated receptors leads to the formation of a receptor-ligand complex activating Ret receptor of tyrosine kinase family, which is only expressed in dopaminergic neurons, playing an important role in Parkinson’s disease, via its association with the essential protein encoded genes. Furthermore, the review establishes delivery aspects, like ventricular delivery of recombinant GDNF, intraparenchymal and intraputaminal delivery using infusion catheters. The review highlights problems and challenges of GDNF delivery, and essential measures to overcome them, like gene therapy combinations, optimization of delivery vectors, newer targeting devices, motor symptoms curbing focused ultrasound techniques, modifications in patient selection criteria and development of novel delivery strategies based on liposomes and encapsulated cells, to promote safe and effective delivery of neurotrophic factor and establishment of routine treatment therapy for patients.

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