Integrative omics: A novel approach to unravelling the complex panoramic landscape of Rett syndrome
Rett syndrome is a rare severe neurodevelopmental disorder, caused by mutations in the MECP2 gene and mainly affects females.
Treatment is purely symptomatic and despite 57 clinical trials, there is still no curative treatment.
The paucity of any disease modifying therapeutic entering the clinic is largely due the lack of useful clinical biomarkers and a complete understanding of the complex underlying disease pathophysiology and function of MeCP2, where over 600 disease causing variants in the gene have been reported.
Over the past few years, the application of high-throughput approaches known as “omics” (e g , genomics, transcriptomics, proteomics, and meta olomics), has developed rapidly and revolutionised both the diagnosis and the understanding of the pathophysiology of many neurological disorders, by providing an unbiased identification of disease drivers, biomarkers, and targets for potential therapeutic strategies. Today, given the rapidly decreasing costs of omic technologies, the increasing standardization of protocols, and the rapid turn-around time, these technologies are emerging as a powerful addition to investigative diagnostics.
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This project identifies potential disease drivers, drug targets and clinical biomarkers that can predict disease state, disease severity, and responses to treatments.
By harnessing the power of omic platforms, and using analytical and computational technologies, the research team set out to dissect the molecular complexity of Rett syndrome, and identify genes, proteins, metabolites and cellular pathways from blood that are differentially dysregulated among patients in the cohort (relative to controls) in an unbiased approach. This will lead to preclinical validation, the initiation of transformative Phase I clinical trials and the translation of novel therapeutics from clinical trials into clinical care.
This project has been able to leverage results and findings from the earlier funded Luminesce Alliance Innovation Project Translating disease severity biomarkers into the clinic for Rett syndrome. This earlier research project analysed blood metabolome in a cohort of Rett syndrome and normal neurotypical control individuals and incorporated analysis of omic technologies, specifically, transcriptomics, proteomics and phospho-proteomics.
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Lead Investigator
- Associate Professor Wendy Gold
Research Team
- Mark Graham, Children’s Medical Research Institute
- Adviye Ayper Tolun, Sydney Children’s Hospitals Network
- Ashley Hertzog, Sydney Children’s Hospitals Network
- Associate Professor Carolyn Ellaway, Sydney Children’s Hospitals Network
- Alexander Wykes, Children’s Medical Research Institute
- Florencia Haase, Sydney Children’s Hospitals Network
- Brain Gloss, Westmead Institute for Medical Research
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Bioinformatic analyis leads to evidence of disease drivers, drug targets and clinical biomarkers that will predict disease state, disease severity, and ultimately treatment efficacy for individuals with Rett syndrome.
In this project, bioinformatic analysis using the MixOmics platform identified dysregulated genes, proteins and metabolites in the Rett patient blood samples compared to the healthy controls. Several key molecules aligning with known disease aetiology were identified, including some previously reported in the literature and some novel molecules.
While some of these molecules are known to be dysregulated in Rett syndrome, the team not only found metabolites that have not previously been reported to be dysregulated in Rett syndrome, but when measured their relative ratio’s, a significant decrease was observed, demonstrating a novel approach in which to use biomarkers to predict a diseased state in Rett syndrome.
This finding is particularly exciting as it enables patient blood to be used to easily measure a marker of disease; which may play a critical role in reliable and comprehensive disease diagnosis and prediction of therapeutic outcomes. The next steps are to expand this study to a larger cohort and test the sensitivity and specificity of these biomarkers.
This project has also generated a significant amount of evidence that will be used to progress toward the long term outcomes of:
• biomarkers and disease drivers that can predict therapeutic efficiency
• ‘druggable’ targets as potential therapies for Rett syndrome
• supporting the initiation of a transformative Phase I clinical trial for Rett syndrome translating novel therapeutics from clinical trials into clinical care.The evidence generated in this research will support the development of intellectual property (IP) centred around novel therapeutic applications for Rett syndrome.
Increased Capability and Capacity – Bioinformatics Workforce
This research initiative highlights the importance of investing in a specialised skill set to address the future demands of analysing omic datasets. To meet this requirement, dedicated efforts were directed towards building workforce capability and capacity.Through Luminesce Alliance funding and training, a Research Assistant was equipped to handle various tasks, including blood collection, storage, RNA and protein extraction, as well as bioinformatic analysis. Additionally, the project engaged a PhD candidate, whose involvement was also supported by a previous Luminesce Alliance Innovation-funded project. This collaborative approach demonstrates a commitment to nurturing expertise and facilitating meaningful contributions to the field.
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2 manuscripts in preparation (reflecting the two innovation projects, topics are outcomes from the mitokine analysis, and Outcomes from the biomarker study).
2 invited presentations: Neurodrug seminar at University of Sydney 28 June 2023, and Childhood Dementia Initiative webinar in October 2023
2 conference presentations:
• Human Genetics Society of Australasia, November 2022
• 2023 American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting Salt Lake City, Utah, March 2023