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Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia Leading Research. Delivering Hope.Open Medicine Foundation® Canada
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Stress-Activated MicroRNAs
in ME / CFS Pathogenesis

The Problem

Myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) is a multi-systemic complex chronic disease exhibiting a clinical heterogeneity as main symptoms vary between affected individuals and also overtime. This situation adds to the complexity to decipher its causes and mechanisms as well as to find potential therapeutic targets. Furthermore, severely affected persons with ME / CFS are rarely being investigated.

Expected Health Impacts
Identifying a specific microRNA signature in ME / CFS will aid in the development of disease risk prediction and improve the clinical stratification of symptomatic patients. nnUltimately, discovery of biomarkers may lead to diagnoses that are more accurate, disease prevention measures, and indications on how to treat ME / CFS effectively.

OUR HYPOTHESIS

We designed a clinical intervention, safely producing a post-exertional malaise (PEM), a hallmark symptom of ME / CFS. We hypothesized that a standardized stress-test inducing PEM, will reveal a more specific disease signature associated with ME / CFS symptoms. In that context, we investigated the role of circulating microRNAs, which are small non-coding RNA molecules that can be detected in the blood as well as in other biological fluids.

WHY THIS STUDY MATTERS FOR ME

Studying microRNAs might help to bridge the conceptual gap between genetic predisposition and environmental factors causing ME / CFS or exacerbating specific symptoms. Equally important, the design of a portable clinical intervention allows investigating severely ill persons with ME / CFS, especially the ones that are housebound.

OUR KEY FINDINGS

A man on a stationary bike participates in a stress test.

  • This strategy led us to identify 32 circulating microRNAs in a case-control cohort.
  • Several of the miRNAs identified in our discovery cohort are associated with inflammation, regulation of immunity and/or a physiological response to exercise (endurance regulators).
  • Implementation of bioinformatics tools like Machine Learning algorithm (Random Forest Algorithm) led to a validation of a first diagnostic panel of 8 microRNAs (miR-28-5p, miR-29a-5p, miR-127-3p, miR-140-5p, miR-374b-5p, miR-486-5p, miR-3620-3p and miR-6819-3p) using a dataset of individuals with ME / CFS and matched healthy controls.
  • This panel has a predictive accuracy of 90% with a sensitivity of 100% and a specificity of 75% when the expression of each microRNA is compared after the stess-test versus their respective values at baseline (without stimulation). Conversely, when only the baseline values are used (without the stress-test), the predictive accuracy is lowered to 60% with a sensitivity of 71% and a specificity of 33% (non-specific). These preliminary results clearly indicated the superiority of our stress-test approach to reveal the molecular signature underlying ME / CFS.
  • This approach led also to an unbiased method to separate the persons with ME / CFS, called clustering, along three distinct clusters showing specific correlations between each cluster and symptom severity. Indeed, persons with ME / CFS classified in cluster 1 exhibit less general fatigue than those classified into cluster 2 and 3, while individuals in cluster 3 suffer of more severe sleep disturbances and PEM.
  • Interestingly, high expression of specific circulating microRNAs could help in predicting the respond toward specific treatment like Ampligen, Rituximab and many others.
  • To find out more about the outcomes of this study, read Profile of Circulating MicroRNAspaper.•The next phase of our investigation into microRNAs continued with the MAESTRO project.

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Microvesicles and viral sequencing
Microvesicles are a type of extracellular vesicle that is released from the cell membrane. Vesicles are small, fluid-filled sacs or vacuoles within the body. Sequencing is a technique used to determine the exact sequence of bases (A, C, G, and T) in a DNA (or viral) molecule.
NMR Metabolomics
NMR (Nuclear Magnetic Resonance) is an instrument/tool used to perform metabolic studies, metabolic profiling, and metabolomics in biofluids and tissues for more than 40 years using magnetic fields. There is a very close connection between metabolic measurements and NMR. This connection has flourished because of NMR’s many unique strengths for characterizing complex mixtures’ chemical composition.
Proteomics
The large-scale study of proteins, which are large, complex molecules that are required for structure, function, and regulation of the human body's tissues and organs.
Autoantibodies
Antibodies that react with self-molecules and that occur in healthy individuals and are referred to as natural antibodies or autoantibodies.
Extracellular DNA for viral reactivation and Mitochondrial DNA
exDNA (extracellular DNA), exDNA is often secreted actively and is used to perform several tasks, thereby offering an attractive target or tool for biotechnological, medical, environmental, and general microbiological applications. Viruses are intracellular parasites that rely to a significant extent on the host cell for replication. Viral reactivation occurs when an active replication of the viral genome results in a lytic (degradation of the cell) infection characterized by the release of new progeny (descendant) virus particles.
Immune cell profiling
The immune system has many important regulatory roles in disease development and progression. Given the emergence of effective immune therapies, reliable predictors of response are needed. Immune cell profiling determines response by evaluating immune cell populations from treated and untreated samples. For our purposes, we will evaluate the white blood cell response to the viral infection using a process called “Cytof.”
Leukocyte Genomics
A leukocyte is a colorless cell circulating in the blood and body fluids and is involved in counteracting foreign substances and disease. A genome is all genetic material of an organism. Genomics is a biology field focusing on the structure, function, evolution, mapping, and editing of genomes. Therefore, leukocyte genomics is the study of all genetic material of leukocytes.
Metabolomics
Metabolomics is a way to study metabolism – that is, through measuring amounts of the metabolites (small molecules) produced by our bodies as we convert food into energy and other molecules that our cells need to survive. Metabolomics technology is ‘large-scale,’ meaning that several thousand metabolites can be measured from a single sample of e.g., blood or urine.
Micro RNA
Cells use Micro RNA to control whether a particular gene is making too much, too little or the normal amount of its protein at a particular time.