Gene Therapies for Parkinson’s Disease

Author(s):  
Martha C. Bohn ◽  
Derek L. Choi-Lundberg
2021 ◽  
pp. 1-6
Author(s):  
Mark Tomishima ◽  
Agnete Kirkeby

After many years of preclinical development, cell and gene therapies have advanced from research tools in the lab to clinical-grade products for patients, and today they constitute more than a quarter of all new Phase I clinical trials for Parkinson’s disease. Whereas efficacy has been convincingly proven for many of these products in preclinical models, the field is now entering a new phase where the functionality and safety of these products will need to stand the test in clinical trials. If successful, these new products can have the potential to provide patients with a one-time administered treatment which may alleviate them from daily symptomatic dopaminergic medication.


ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110097
Author(s):  
Kui Cui ◽  
Fan Yang ◽  
Turan Tufan ◽  
Muhammad U. Raza ◽  
Yanqiang Zhan ◽  
...  

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.


2009 ◽  
Vol 64 (S2) ◽  
pp. S122-S138 ◽  
Author(s):  
Ole Isacson ◽  
Jeffrey H. Kordower

2020 ◽  
Vol 54 (3) ◽  
pp. 220-231
Author(s):  
Massimo S. Fiandaca ◽  
Russell R. Lonser ◽  
J. Bradley Elder ◽  
Mirosław Ząbek ◽  
Krystof S. Bankiewicz

2007 ◽  
Vol 35 (2) ◽  
pp. 428-432 ◽  
Author(s):  
E. Dowd ◽  
S.B. Dunnett

The different populations of dopaminergic neurons located in the ventral mesencephalon have long been associated with distinct functional roles. The nigrostriatal projection is considered necessary for efficient motor performance, while the mesolimbocortical projection is usually associated with reward signalling. However, a number of recent studies in our laboratory suggest that the divergence between these two functions of dopamine is not as delineated as it may once have seemed. In these experiments, we have been developing improved behavioural methods for assessing the nature of the deficit in rats with unilateral dopamine lesions, as well as the efficacy of various experimental cell and gene therapies for Parkinson's disease. The behavioural task we selected is a lateralized nose-poking task in which rats are trained to respond to stimulus lights on either side of their heads. This task not only allows us to accurately measure aspects of motor performance, but, because it requires extensive training, it also allows us to assess aspects of motor learning. The concurrence of motor performance parameters (which are considered to be dependent on striatal dopamine) and motor learning parameters (which are thought to be dependent on mesolimbocortical reward signalling) within the same task has revealed some surprising consequences of dopamine lesions and neuroprotective/neuroreparative approaches to repair in rat models of Parkinson's disease. The data generated using this task suggest that the motor deficits that occur as a consequence of dopamine lesions may be downstream of a deficit in reward signalling. If so, this could redefine our perception of the role of dopamine in controlling motor function.


Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1840
Author(s):  
Jannik Prasuhn ◽  
Norbert Brüggemann

Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.


2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Soyeon Park

Parkinson’s Disease was first introduced by James Parkinson in 1817. Since then, major strides have been made in the development of its treatment. Early treatments were dominated by traditional and complementary therapies, which were largely serendipitous and observation-based. Especially, the use of anticholinergics by Jean-Martin Charcot and his student Ordenstein prevailed in the late 20th century. Current drug-based therapies manifest in the form of levodopa accompanied by dopamine agonist, COMT inhibitor, or MAO-B inhibitor, for the purpose of reducing the levodopa-induced symptom fluctuation. In terms of surgical treatment, while ablative surgeries in the brain have been abandoned due to high mortality rate in the late 1900s, Deep Brain Stimulation in the subthalamic nucleus or internal globus pallidus has mostly replaced ablative surgeries since its introduction in 1987. Current research topics include non-dopaminergic agents for motor fluctuation reduction, transplantation of dopaminergic neurons, gene therapies using viral vectors, reduction of alpha-synuclein neurotoxicity, and neuroprotective therapies. Especially, due to the fact that the etiology of the disease is yet to be elucidated, neuroprotective therapies aimed at slowing or stopping disease progression are of particular interest. It is suggested that future research should aim towards clarifying the cause of the disease, for the development of a treatment that can permanently halt or reverse Parkinson’s Disease-related neurodegeneration.


2021 ◽  
Vol 22 (17) ◽  
pp. 9241
Author(s):  
David Arango ◽  
Amaury Bittar ◽  
Natalia P. Esmeral ◽  
Camila Ocasión ◽  
Carolina Muñoz-Camargo ◽  
...  

CRISPR is a simple and cost-efficient gene-editing technique that has become increasingly popular over the last decades. Various CRISPR/Cas-based applications have been developed to introduce changes in the genome and alter gene expression in diverse systems and tissues. These novel gene-editing techniques are particularly promising for investigating and treating neurodegenerative diseases, including Parkinson’s disease, for which we currently lack efficient disease-modifying treatment options. Gene therapy could thus provide treatment alternatives, revolutionizing our ability to treat this disease. Here, we review our current knowledge on the genetic basis of Parkinson’s disease to highlight the main biological pathways that become disrupted in Parkinson’s disease and their potential as gene therapy targets. Next, we perform a comprehensive review of novel delivery vehicles available for gene-editing applications, critical for their successful application in both innovative research and potential therapies. Finally, we review the latest developments in CRISPR-based applications and gene therapies to understand and treat Parkinson’s disease. We carefully examine their advantages and shortcomings for diverse gene-editing applications in the brain, highlighting promising avenues for future research.


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