scholarly journals Gene Therapy for Parkinson’s Disease Associated with GBA1 Mutations

2021 ◽  
pp. 1-6
Author(s):  
Asa Abeliovich ◽  
Franz Hefti ◽  
Jeffrey Sevigny
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Disease Risk ◽  
Age Of Onset ◽  
Normal Range ◽  
Genetic Studies ◽  
Lysosomal Dysfunction ◽  
The Brain

Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson’s disease. Among the lysosomal genes involved, GBA1, has the largest impact on Parkinson’s disease risk. Deficiency in the GBA1 encoded enzyme glucocerebrosidase (GCase) leads to the accumulation of the GCase glycolipid substrates glucosylceramide and glucosylsphingosine and ultimately results in toxicity and inflammation and negatively affect many aspects of Parkinson’s disease, including disease risk, the severity of presentation, age of onset, and likelihood of progression to dementia. These findings support the view that re-establishing normal range levels of GCase expression and enzyme activity may reduce the progression of Parkinson’s disease in patients carrying GBA1 mutations. Studies in mouse models indicate that PR001, a rAAV9 vector-based gene therapy designed to deliver a functional GBA1 gene to the brain, suggest that this therapeutic approach may slow or stop disease progression. PR001 is currently being evaluated in clinical trials with Parkinson’s disease patients carrying GBA1 mutations.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Madison E. Hoes ◽  
Anastazja M. Gorecki ◽  
Frances Theunissen ◽  
Abigail L. Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

scholarly journals The Phenomenon of Brain World : Neuroculture in the Making by Patients with Parkinson’s Disease

2018 ◽  
Vol 10 (1) ◽  
pp. 102-114
Author(s):  
Markus Idvall
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Biomedical Research ◽  
Daily Life ◽  
Chronically Ill ◽  
Main Body ◽  
Embodied Experience ◽  
Clinical Neuroscience ◽  
The Brain

The aim of this article is to explore how the phenomenon of brain world, as a symptom of a possible emerging neuroculture, is perceived and enacted by patients with Parkinson’s disease, who, in their daily life, are subjected to neuroscience, most often as chronically ill individuals hoping for a cure, but also in some instances as participants in clinical trials. The article is based on a multifaceted ethnographic material that maps the experiences of biomedical research among patients with Parkinson’s. The main body of material consists of interviews carried out in 2012 and 2015, and comprises 19 transcripts of recorded conversations, conducted in groups as well as individually. The article argues that the exposure of the patients to clinical neuroscience gives birth to neuroculture. A materialist-discursive phenomenon called brain world—perceptions and enactments of the brain—is problematized on the basis of how patients cope with and reflect on their chronic illness in everyday life situations and in confrontation with clinical neuroscience. The embodied experience of the illness operates as the route into the brain world and also becomes the ground for how this world is featured with specific properties. Brain world is in this respect a contradictory entity: both plastic and fragile, both accessible and too complex, both strange and known. Most of all, brain world, in the eyes of the patients, relates to a territory still dominated by neuroscientists.

scholarly journals Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Michele Perni ◽  
Annemieke van der Goot ◽  
Ryan Limbocker ◽  
Tjakko J. van Ham ◽  
Francesco A. Aprile ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Rate Control ◽  
Neurological Disorders ◽  
Age Of Onset ◽  
Wild Type ◽  
C Elegans ◽  
A53t Mutation ◽  
A30p Mutation

The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two C. elegans models of PD (PDA30P and PDA53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PDWT). PDA30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PDA53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PDA30P worms compared to PDA53T and PDWT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PDA53T and PDWT worms, but had less marked effects in PDA30P. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PDA30P, PDA53T and PDWT worms. These results illustrate the use of these two C. elegans models in fundamental and applied PD research.

scholarly journals Next-Generation Gene Therapy for Parkinson’s Disease Using Engineered Viral Vectors

2021 ◽  
pp. 1-9
Author(s):  
Tomas Björklund ◽  
Marcus Davidsson
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Genome Editing ◽  
Viral Vectors ◽  
State Of The Art ◽  
The State ◽  
Next Generation ◽  
Suitable Vector

Recent technological and conceptual advances have resulted in a plethora of exciting novel engineered adeno associated viral (AAV) vector variants. They all have unique characteristics and abilities. This review summarizes the development and their potential in treating Parkinson’s disease (PD). Clinical trials in PD have shown over the last decade that AAV is a safe and suitable vector for gene therapy but that it also is a vehicle that can benefit significantly from improvement in specificity and potency. This review provides a concise collection of the state-of-the-art for synthetic capsids and their utility in PD. We also summarize what therapeutical strategies may become feasible with novel engineered vectors, including genome editing and neuronal rejuvenation.

scholarly journals Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

2015 ◽  
Vol 17 ◽  
Author(s):  
Martin J. Kelly ◽  
Gerard W. O'Keeffe ◽  
Aideen M. Sullivan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Neurotrophic Factors ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Viral Vectors ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
The Brain

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

scholarly journals Parkinson’s Disease in Central Asian and Transcaucasian Countries: A Review of Epidemiology, Genetics, Clinical Characteristics, and Access to Care

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Rauan Kaiyrzhanov ◽  
Mie Rizig ◽  
Akbota Aitkulova ◽  
Nazira Zharkinbekova ◽  
Chingiz Shashkin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Characteristics ◽  
Large Scale ◽  
Age Of Onset ◽  
Genetic Studies ◽  
Related Data ◽  
Central Asian ◽  
The Mean ◽  
Made In

Our understanding of Parkinson’s disease (PD) has significantly accelerated over the last few years, but predominant advances have been made in developed, Western countries. Little is known about PD in the Central Asian (CA) and Transcaucasian (TC) countries. Here, we review the clinical characteristics, treatments used, epidemiology, and genetics of PD in CA and TC countries via a methodological search in MEDLINE, EMBASE, Scopus, Web of Science, and Google Scholar databases. For the acquisition of PD care-related data, the search was extended to the local web resources. Our findings showed that PD prevalence in the region is averaging 62 per 100,000 population. The mean age of onset is 56.4 ± 2.8 in females and 63.3 ± 3.5 in males. Large-scale national studies on PD prevalence from the region are currently lacking. A limited number of genetic studies with small cohorts and inconclusive results were identified. The G2019S LRRK2 mutation, the commonest mutation in PD worldwide, was found in 5.7% of patients with idiopathic PD and 17.6% of familial cases in 153 Uzbek patients. Our review highlighted systematic deficiencies in PD health care in the region including lacks of neurologists specializing in PD, delays in PD diagnosis, absence of specialized PD nurses and PD rehab services, limited access to PD medications and surgery, and the unavailability of PD infusion therapies. Overall, this article demonstrated the paucity of data on this common neurological disorder in CA and TC countries and identified a number of healthcare areas that require an urgent consideration. We conclude that well-designed large-scale epidemiological, genetic, and clinical studies are desperately needed in this region. Healthcare professionals, local and national institutions, and stakeholders must come together to address deficiencies in PD healthcare systems in CA and TC countries.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease.

2020 ◽  
Author(s):  
Megan Bakeberg ◽  
Madison Hoes ◽  
Anastazja Gorecki ◽  
Frances Theunissen ◽  
Abigail Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

Abstract Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not in the Australian cohort. Variation in the TOMM40 structural variant was not associated with PD risk, but may be a modifying factor for age of symptom onset in some PD populations, warranting further investigation.

scholarly journals Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 4966 ◽  
Author(s):  
Shani Blumenreich ◽  
Or B. Barav ◽  
Bethan J. Jenkins ◽  
Anthony H. Futerman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurological Diseases ◽  
Critical Role ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Regulatory Processes ◽  
Lysosomal Dysfunction ◽  
The Brain ◽  
Shed Light

The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.

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