Dataset Information

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein.

ABSTRACT: The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (?-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of ?-syn targeting therapies. This consensus white paper provides a translational framework, from the selection of animal models and associated end-points to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of ?-syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting ?-syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting ?-syn.

SUBMITTER: Merchant KM

PROVIDER: S-EPMC6398545 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein.

Merchant Kalpana M KM Cedarbaum Jesse M JM Brundin Patrik P Dave Kuldip D KD Eberling Jamie J Espay Alberto J AJ Hutten Samantha J SJ Javidnia Monica M Luthman Johan J Maetzler Walter W Menalled Liliana L Reimer Alyssa N AN Stoessl A Jon AJ Weiner David M DM

Journal of Parkinson's disease 20190101 1

The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (α-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the ...[more]

PMID: 30400107

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Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Project description:Caudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson's disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson's disease patients, and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here, we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48 h with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists' effects after 24 hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real-time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48 hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. Toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription, and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here, we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson's disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut.

Dataset Information

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein.

Publications

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein.

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