scholarly journals Drug Repurposing for Parkinson’s Disease: The International Linked Clinical Trials experience

2021 ◽  
Vol 15 ◽  
Author(s):  
Simon R. W. Stott ◽  
Richard K. Wyse ◽  
Patrik Brundin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Drug Repurposing ◽  
Disease Modification

The international Linked Clinical Trials (iLCT) program for Parkinson’s to date represents one of the most comprehensive drug repurposing programs focused on one disease. Since initial planning in 2010, it has rapidly grown – giving rise to seven completed, and 15 ongoing, clinical trials of 16 agents each aimed at delivering disease modification in Parkinson’s disease (PD). In this review, we will provide an overview of the history, structure, process, and progress of the program. We will also present some examples of agents that have been selected and prioritized by the program and subsequently evaluated in clinical trials. Our goal with this review is to provide a template that can be considered across other therapeutic areas.

scholarly journals Recent developments in the treatment of Parkinson's Disease

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 862 ◽  
Author(s):  
Thomas B Stoker ◽  
Roger A Barker
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Treatment Options ◽  
Freezing Of Gait ◽  
Safety Data ◽  
Neuronal Loss ◽  
Drug Repurposing ◽  
Disease Course ◽  
Novel Therapeutic

Parkinson’s disease (PD) is a common neurodegenerative disease typified by a movement disorder consisting of bradykinesia, rest tremor, rigidity, and postural instability. Treatment options for PD are limited, with most of the current approaches based on restoration of dopaminergic tone in the striatum. However, these do not alter disease course and do not treat the non-dopamine-dependent features of PD such as freezing of gait, cognitive impairment, and other non-motor features of the disorder, which often have the greatest impact on quality of life. As understanding of PD pathogenesis grows, novel therapeutic avenues are emerging. These include treatments that aim to control the symptoms of PD without the problematic side effects seen with currently available treatments and those that are aimed towards slowing pathology, reducing neuronal loss, and attenuating disease course. In this latter regard, there has been much interest in drug repurposing (the use of established drugs for a new indication), with many drugs being reported to affect PD-relevant intracellular processes. This approach offers an expedited route to the clinic, given that pharmacokinetic and safety data are potentially already available. In terms of better symptomatic therapies that are also regenerative, gene therapies and cell-based treatments are beginning to enter clinical trials, and developments in other neurosurgical strategies such as more nuanced deep brain stimulation approaches mean that the landscape of PD treatment is likely to evolve considerably over the coming years. In this review, we provide an overview of the novel therapeutic approaches that are close to, or are already in, clinical trials.

scholarly journals Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Christian U. von Linstow ◽  
Ziv Gan-Or ◽  
Patrik Brundin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Disease Progression ◽  
Alpha Synuclein ◽  
Motor Symptoms ◽  
Disease Modification ◽  
Risk Variants ◽  
Non Motor Symptoms

Abstract Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

Recent Advances in Drug Repurposing for Parkinson’s Disease

2019 ◽  
Vol 26 (28) ◽  
pp. 5340-5362 ◽  
Author(s):  
Xin Chen ◽  
Giuseppe Gumina ◽  
Kristopher G. Virga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cost Effective ◽  
New Drugs ◽  
Recent Advances ◽  
Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

scholarly journals Bringing Advanced Therapies for Parkinson’s Disease to the Clinic: The Scientist’s Perspective

2021 ◽  
pp. 1-6
Author(s):  
Mark Tomishima ◽  
Agnete Kirkeby
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Phase I Clinical Trials ◽  
Preclinical Models ◽  
Preclinical Development ◽  
Dopaminergic Medication ◽  
Gene Therapies ◽  
Advanced Therapies ◽  
New Phase

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.

Neuroprotective agents for clinical trials in Parkinson's disease: A systematic assessment

Neurology ◽  
2003 ◽  
Vol 60 (8) ◽  
pp. 1234-1240 ◽  
Author(s):  
B.M. Ravina ◽  
S.C. Fagan ◽  
R.G. Hart ◽  
C.A. Hovinga ◽  
D.D. Murphy ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Neuroprotective Agents ◽  
Systematic Assessment

Parkinson's disease and convergence insufficiency: a mini-review

2021 ◽  
Vol 1 (3) ◽  
pp. 108-111
Author(s):  
Mashael Al-Namaeh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Control Group ◽  
Healthy Controls ◽  
Inclusion Criteria ◽  
Medline Search ◽  
Convergence Insufficiency ◽  
Eye Examination ◽  
The Relationship

Background: A key manifestation of Parkinson’s disease (PD) is visual impairment. Cognitive impairment has been found to overlap with convergence insufficiency (CI) in patients with PD and is associated with significantly greater near point convergence (NPC) distance. Difficulty in reading and diplopia were the most common symptoms of CI in PD. The prevalence of CI is greater among patients with PD. Therefore, this study aimed to assess the relationship between PD and CI. Methods: Studies that had included data on CI, NPC, or both were selected by searching PubMed/MEDLINE and clinicaltrails.gov, without any timeline or language limitation. The following terms were used in PubMed/MEDLINE search: ‘Clinical Trials’, ‘Parkinson’s Disease’, and ‘Convergence Insufficiency’. For clinical trials.gov database, the terms ‘Parkinson’s Disease’, ‘Convergence Insufficiency’, and ‘Completed Studies’ were used. Only those studies with control subjects were included. PubMed/MEDLINE search yielded 1,563 articles, but no article was found in the clinical trails.gov search. Twelve articles met the inclusion criteria, among which nine articles were selected as they had data on CI or NPC distance (cm), and PD.   Results: Overall, there were 1,563 articles; among them, 12 articles met the inclusion criteria. Nine articles were selected based on their data concerning CI or NPC distance (cm) and PD. Relative to the control group, the PD group had high CI. In addition, PD group showed increase in NPC distance than the control group. Conclusions: These data suggest that the patients with PD had an increased likelihood of developing CI visual symptoms, and increased NPC distance than healthy controls. These findings indicate that regular eye examination is very important for patients with PD.

Longitudinal Change and Progression Indicators Using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale in Two Independent Cohorts with Early Parkinson’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Michael Bartl ◽  
Mohammed Dakna ◽  
Sebastian Schade ◽  
Tamara Wicke ◽  
Elisabeth Lang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Rating Scale ◽  
De Novo ◽  
Longitudinal Change ◽  
Single Center ◽  
Square Roots ◽  
Disease Rating

Background: The MDS-Unified Parkinson’s disease (PD) Rating Scale (MDS-UPDRS) is the most used scale in clinical trials. Little is known about the predictive potential of its single items. Objective: To systematically dissect MDS-UPDRS to predict PD progression. Methods: 574 de novo PD patients and 305 healthy controls were investigated at baseline (BL) in the single-center DeNoPa (6-year follow-up) and multi-center PPMI (8-year follow-up) cohorts. We calculated cumulative link mixed models of single MDS-UPDRS items for odds ratios (OR) for class change within the scale. Models were adjusted for age, sex, time, and levodopa equivalent daily dose. Annual change and progression of the square roots of the MDS-UDPRS subscores and Total Score were estimated by linear mixed modeling. Results: Baseline demographics revealed more common tremor dominant subtype in DeNoPa and postural instability and gait disorders-subtype and multiethnicity in PPMI. Subscore progression estimates were higher in PPMI but showed similar slopes and progression in both cohorts. Increased ORs for faster progression were found from BL subscores I and II (activities of daily living; ADL) most marked for subscore III (rigidity of neck/lower extremities, agility of the legs, gait, hands, and global spontaneity of movements). Tremor items showed low ORs/negative values. Conclusion: Higher scores at baseline for ADL, freezing, and rigidity were predictors of faster deterioration in both cohorts. Precision and predictability of the MDS-UPDRS were higher in the single-center setting, indicating the need for rigorous training and/or video documentation to improve its use in multi-center cohorts, for example, clinical trials.

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