Annual progress reports of funded research

GNT1199363: Using ‘omics' to unravel the pathophysiology and repurpose drugs to treat ME/CFS

  • Professor Ken Walder (Chief Investigator A)
  • Deakin University
  • Budget: $1,083,010
  • Funding Period: 2020-2025

Project synopsis

This project will utilise cutting edge technologies to better understand the mechanisms that contribute to the symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and will use a proven methodological approach to repurpose existing drugs for the treatment of this disorder. Cells collected from blood of participants with ME/CFS will be used to investigate mitochondrial function and cellular metabolism using multiple methods. Gene expression signature screening will be used to screen for drugs that can be repurposed for the treatment of ME/CFS. By testing against drugs that are off-patent and have known clinical safety profile, possible treatment candidates can quickly progress to clinical testing and bring benefit to those suffering from ME/CFS in the short term.

Progress report as of 30 April 2023

A total of 62 participants have been recruited into the study (28 with ME/CFS and 34 healthy controls). The median age of the ME/CFS participants was 43, and 85% were female. The ME/CFS participants had more medical co-morbidities than the healthy control group, and used more medications. As expected, the ME/CFS subjects had lower hand grip strength, and on repeat testing their hand grip strength deteriorated more rapidly than that of the healthy control participants. Work has commenced on the blood samples to generate induced pluripotent stem cells, which will then be differentiated into cortical networks for experiments. These experiments are expected to commence in late 2023 or early 2024.

 

GNT1199502: Ion channel dysfunction in the pathophysiology of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: diagnostic biomarkers, therapeutic targets and treatments

  • Professor Sonya Marshall-Gradisnik (Chief Investigator A)
  • Griffith University
  • Budget: $1,460,700
  • Funding Period: 2021-2025

Project synopsis

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterised by persistent debilitating fatigue and multi-system impairments underpinning the clinical severity phenotypes of ME/CFS. The pathophysiology is unknown and there are no confirmed diagnostic tests or effective therapeutic treatments. Cellular dysfunction suggests that the understanding of the pathophysiology of ME/CFS could assist in identifying novel biomarkers and targeted pharmacotherapeutic treatments.

This multicentre study aims to identify the pathophysiology of ME/CFS and biomarkers for the potential development of a diagnostic test. It will investigate existing registered drugs for potential treatments and application for future clinical trials. The findings will assist in the revision of clinical guidelines, and improve outcomes for ME/CFS patients and reduce health care costs worldwide.

Progress report as of 30 April 2023

The research findings have successfully identified transient receptor potential (TRP) ion channels, including TRP melastatin (M) 3 and TRPM7, in the pathomechanism of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A key research outcome form this reporting period demonstrated the diagnostic accuracy of TRPM3 dysfunction at 86% (receiver operating characteristics) for the potential development of a diagnostic screening test for ME/CFS.

The identification of TRPM3 dysfunction also provides a potential therapeutic target and recent research findings have demonstrated the potential benefit of repurposing low dose naltrexone (LDN) in restoring TRPM3 function and improving health outcomes.

Data from this grant has generated six publications1-6 and has been presented at nine national and international conferences where three National Centre for Neuroimmunology and Emerging Diseases (NCNED) investigators received research awards in addition to one podcast. This grant has been essential in leverage two successful grants totalling $6.9 million AUD. The applications of this research in the field of Long COVID has resulted in an Australian provisional patent (ID: 2022902253).

The impact of this research is far reaching whereby project outcomes and publications have resulted in global recognition. CIA and post-doc are participating in writing the British clinical guidelines for ME/CFS and have been requested by the National Academies, USA to write a report for USA Health Services and National Institutes for Health on the evidence of Long COVID and ME/CFS. This report is aimed at accelerating the progress in research, diagnosis, and treatment of these diseases. CIA and NCNED investigators submitted a report to the Inquiry into Long COVID and Repeated COVID Infections. NCNED continues to translate their research outcomes into policy through the development of a Health Policy Issues Brief detailing patient experiences with Long COVID in Australia in collaboration with the Deeble Institute, Canberra.

Publications and other Resources

1Eaton-Fitch N, Du Preez S, Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med 2022;20:94. https://doi.org/10.1186/s12967-022-03297-8. 

2Sasso EM, Muraki K, Eaton-Fitch N, Smith P, Lesslar OL, Deed G, et al. Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients. Mol Med 2022;28:98. https://doi.org/10.1186/s10020-022-00528-y. 

3Magawa CT, Eaton-Fitch N, Balinas C, Sasso EM, Thapaliya K, Barnden L, et al. Identification of transient receptor potential melastatin 3 proteotypic peptides employing an efficient membrane protein extraction method for natural killer cells. Front Physiol 2022;13:947723. https://doi.org/10.3389/fphys.2022.947723. 

4Cabanas H, Muraki K, Eaton-Fitch N, Staines DR, Marshall-Gradisnik S. Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment. Front Immunol 2021;12:687806. https://doi.org/10.3389/fimmu.2021.687806. 

5Du Preez S, Eaton-Fitch N, Cabanas H, Staines D, Marshall-Gradisnik S. Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Int J Environ Res Public Health 2021;18:11879. https://doi.org/10.3390/ijerph182211879. 

6Eaton-Fitch N, Cabanas H, du Preez S, Staines D, Marshall-Gradisnik S. The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med 2021;19:306. https://doi.org/10.1186/s12967-021-02974-4.

Other resources

 

GNT1200292: Exploring the role of nitrogen metabolism, energy metabolism and mitochondrial function in the pathophysiological mechanisms of paediatric ME/CFS

  • Professor Paul Gooley (Chief Investigator A)
  • University of Melbourne
  • Budget: $784,063.50
  • Funding Period: 2020-2023

Project synopsis

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is diagnosed by its symptoms, which include post-exertional malaise, fatigue, sleep disturbance, pain and cognitive impairment. Currently, there is no diagnostic biomarker, and it is unclear how symptoms arise to form this chronic pathological state. In adults with ME/CFS, a fundamental defect in energy metabolism has been observed. It is hypothesised this leads to increased accumulation of toxic by-products in the mitochondria, which could represent an underlying pathology for ME/CFS. However, research into potential disease mechanisms in adolescents with ME/CFS is severely limited, despite adolescence representing a major age peak in the incidence of ME/CFS.

Paediatric ME/CFS patients diagnosed and/or treated at the Royal Children’s Hospital will be invited to participate in this study. The first step is to collect a blood sample in conjunction with a cognitive assessment, symptom surveys and questionnaires. Consenting participants will be engaged in a longitudinal study with wearable health technology while collecting urine and blood samples from patients over time.

The projected outcomes of this project are to discover novel biomarkers in ME/CFS, understand the extent of energy metabolism dysfunction in ME/CFS, and determine links between metabolism and the onset and fluctuation of symptoms over time to aid in diagnosis, prognosis and treatments outcomes for paediatric ME/CFS.

Progress report as of 30 April 2023

The study has commenced at the Royal Children’s Hospital (RCH) and recruitment has been expanded by establishing secondary recruitment pathways via the Victorian Paediatric Rehabilitation Service and Royal Children’s Hospital private paediatric outpatient clinics. The study recruitment has been advertised through multiple means including a recently approved submission to ‘Emerge Australia’ to advertise on their platforms. Recruitment is ongoing to reach our target for the research study.

The protocol for the multi-disciplinary two-part study design has been developed and has received ethics approval. We have expanded the initial plan to incorporate MRI imaging as part of the project.

Staff, including a neuropsychologist, post-doctoral researcher (project coordinator), research assistant and PhD student, have been recruited to the project. A Paediatric ME/CFS Advisory Board involving families (and patients) with lived experience of ME/CFS has also been established and three meetings have taken place with feedback taken on board.

A protocol paper outlining the study design of this in-depth and multi-disciplinary research has commenced and is expected to be submitted for publication within the next 3-6 months.