Annual progress reports of funded research

Using ‘omics' to unravel the pathophysiology and repurpose drugs to treat ME/CFS (1199363)

  • 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 2024

We decided to stop recruitment and focus on generating the cell lines required for the drug screening work. The decision to stop recruitment was based on the fact that despite continued advertising and promotion of the study we did not receive a single expression of interest for 3 months. At that stage we evaluated the cohort that we had already recruited into the study and decided that the participants available would be more than sufficient to successfully complete the study. The cell work involves generating induced pluripotent stem cells, which are then differentiated into cortical networks or skeletal muscle cells for experiments. These processes are long and technically challenging but are proceeding well. At this stage we have 10 (out of 16) cortical networks in place. We expect to complete cell line generation in July (for CNs – send for NGS) and Oct-Nov for muscle cells, and commence drug screening experiments for both Q1 2025.

 

Ion channel dysfunction in the pathophysiology of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: diagnostic biomarkers, therapeutic targets and treatments (1199502)

  • 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 2024

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) where we continue to investigate potential pharmacotherapeutic interventions targeting these ion channels.

In the previous reporting period we reported the diagnostic accuracy of TRPM3 dysfunction at 86% (receiver operating characteristics) for the potential development of a diagnostic screening test for ME/CFS where we are now developing a high throughput test based upon these findings. In addition, we are collaborating with a diagnostic company to develop a saliva-based ion channel platform for a screening test for ME/CFS that is based upon our provisional patent detailed below.

We continue to investigate potential therapeutic targets as outlined in the proposal where the impact of these research findings has been communicated nationally and internationally to more than 12 million people (official media tracking metrics from Griffith University).

Data from this grant has generated 7 publications.1-7 and has been presented at 5 national and international conferences where 3 National Centre for Neuroimmunology and Emerging Diseases (NCNED) investigators received research awards in addition to one podcast. This grant has been essential in leveraging two successful grants totalling $506,000 AUD. The applications of this research in the field of Long COVID and the overlap with ME/CFS 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 have co-authored the Best Practice Clinical Guidelines for ME/CFS and published by the British Medical Journal. Additionally, the CIA and post-doctoral fellows have written the guidelines for the evidence of Long COVID and ME/CFS for the National Academies for Science, Medicine and Engineering (USA).

NCNED continues to translate their research outcomes into policy and best practice through invitations to present research and clinical pathways for ME/CFS from professional bodies, such as the Australian Doctor and State Primary Health Care Bodies.

Publications, conference abstracts and other resources

1 Baraniuk, J, Marshall-Gradisnik, S and Eaton-Fitch, N. Best Practice Guidelines for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2024), British Medical Journal Open. Link: https://pubmed.ncbi.nlm.nih.gov/38961009/

2 Weigel B, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. Illness presentation and quality of life in myalgic encephalomyelitis/chronic fatigue syndrome and post COVID-19 condition: a pilot Australian cross-sectional study. Qual Life Res. 2024 Jul 3. doi: 10.1007/s11136-024-03710-3.

3 Sasso, EM., Muraki, K., Eaton-Fitch, N., Baraniuk, JN., Smith, P., Jeremijenko, A., Marshall-Gradisnik S. In vitro treatment with Naltrexone restores TRPM3 ion channel function in NK cells from Long Covid patients and ME/CFS, Frontiers in Immunology. Volume 15 – 2024, https://doi.org/10.3389/fimmu.2024.1264702

4 Taccori, A., Maksoud, R., Eaton-Fitch, N., Patel, M., and Marshall-Gradisnik, S. A systematic review and meta-analysis of urinary biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Translational Medicine. 2023. 21(1). Doi:10.1186/212967-023-04295-0.

5 Du Preez, S., Eaton-Fitch, N., Smith, P., and Marshall-Gradisnik, S. Altered TRPM7-dependent calcium influx in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. Biomolecules. 2023. 13(7). 1039. DOI: 10.3390/biom13071039  

6 Maksoud, R., Magawa, C., Eaton-Fitch, N., Thapaliya, K., and Marshall-Gradisnik, S. Biomarkers for ME/CFS: a systemic review. BMC Medicine. 2023. 21(189). DOI: 10.1186/s12916-023-02893-9  

7 Weigel, B., and Haddock, R. 2023. How patient experiences can guide the development of Long COVID health policy. Deeble Issues Brief No 53. Australian Healthcare and Hospitals Association, Australia. Published online 26/09/2023, registered with the Analysis and Policy Observatory (APO) on 28/09/2023.

Invitations from international/national medical bodies or governments for advising for ME/CFS and/or long covid

1 2023, Professor Sonya Marshall-Gradisnik and Dr Natalie Eaton-Fitch invited to write for National Academies – ME/CFS, Long COVID and FM: Overlapping Clinical and Biological Factors - For the review of long-term impacts of COVID-19 committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Invitation by the American Academy for Medicine, Science and Engineering, for the new publication of the new clinical guidelines for ME/CFS.

2 2023, Professor Sonya Marshall-Gradisnik invited to the “Friends of Parliament of ME/CFS, July 2023 to discuss the development for new clinical guidelines for ME/CFS.

3 2024, Professor Sonya Marshall-Gradisnik and Dr Eaton-Fitch, co-authored, with Professor James Baraniuk, Georgetown University, USA, the British Medical Journal Best Practice Clinical Guidelines for ME/CFS.

4 2023, Professor Marshall-Gradisnik invited by Australian Doctor to outline the current research findings and clinical presentation for ME/CFS.

5 2023, Professor Sonya Marshall-Gradisnik and Dr Natalie Eaton-Fitch were invited speaker to present on ME/CFS diagnosis and treatment to ACT GPs (September 2023).

6 2023, Dr Thapaliya and Dr Eaton-Fitch invited to present at QLD Primary Care Public Health Network, (18 October), 2023.

7 2023, Professor Marshall-Gradisnik, invited to present to the ME/CFS and Long COVID Western Australian Taskforce November meeting, (September), 2023.

Additional funds leveraged

2024-2027 ME Research UK (MERUK) Investigating brainstem dysfunction using an ultra-high field scanner (7 Tesla) in ME/CFS patients. L Bamden (CIA), K Thapaliya (CIB), N Eaton-Fitch (CIC) and S Marshall-Gradisnik (CIC). $448,000

2023-2024 Mineral Resources (W.A) Long COVID clinical investigations S Marshall-Gradisnik (CIA). N Eaton-Fitch (CIB) and James Jarman (CIC) $60,000

Radio & TV interviews for ME/CFS research findings and relationship with long covid

Various television and radio interviews (52 in total) have been presented across national media outlets ABC, Seven News and other media outlets. News pieces across all outlets summarising the potential of Naltrexone all contain similar information as the following:

 

Exploring the role of nitrogen metabolism, energy metabolism and mitochondrial function in the pathophysiological mechanisms of paediatric ME/CFS (1200292)

  • 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 12 July 2024

The study is ongoing at the Royal Children’s Hospital (RCH) and recruitment is in progress.

Current consented and completed participants n=39 (20 patients, 19 non-ME/CFS controls). 6 additional patients are in the pre-screening/ booking phase.

Recruitment has been slower due to challenges at the RCH hospital clinic level (our main recruitment avenue). Challenging booking systems at RCH mean the clinicians have regular no shows to clinic, and many of the current cohort of patients seen at RCH and via the Victorian Paediatric Rehabilitation Service (VPRS) live rurally or are in year 12, so are not willing to come to RCH for blood sampling.

In response to this, we have submitted the following project amendments to our ethics committees:

  1. Changes to recruitment. We have expanded recruitment to the wider community to recruit patients who have a clinical diagnosis of ME/CFS.
    Purpose of change: The revised recruitment avenue for the patient cohort aims to expand our recruitment reach, ensuring the timely enrolment of patients and completion of the study. To ensure appropriate diagnosis of ME/CFS, all participants who have not already had their diagnosis confirmed by specialist practitioners at RCH or via VPRS (Monash) will have their diagnosis confirmed by CI A/Prof Adam Scheinberg, an expert clinician at the Royal Children’s Hospital, or AI Dr David Fineberg, General Practitioner who specialises in ME/CFS, to confirm the ME/CFS diagnosis and ensure diagnostic stringency.
  2. Changes to required components for ME/CFS patients. The Clinical assessment (Study Visit) is now optional for ME/CFS participants.
    Purpose of change: The revised optional pathways for ME/CFS patients ensure the clinical trial is more inclusive for patients who have more severe symptoms (for example, housebound) and cannot attend the hospital for various reasons.

These amendments are fast tracking recruitment to ensure timely completion of the study.

A protocol paper outlining the study design of this in-depth and multi-disciplinary research has been prepared and submitted to BMJ Open (details below).

Publications and other resources

Serial Paediatrics Omics Tracking in Myalgic Encephalomyelitis (SPOT-ME): Protocol Paper for a Multidisciplinary Study of Paediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Natalie Thomas, Tracey Chau, Darcy Tantanis, Katherine Huang, Adam Scheinberg, Paul R. Gooley, Elisha K. Josev, Sarah J. Knight, Christopher W. Armstrong. Submitted to BMJ Open. May 2024.