Leading the Future with Circular RNA
SCIENCE
Circular RNAs: Stable signals of brain health and disease
Circular RNAs (circRNAs) are a unique and novel class of non-coding RNA molecules that play key regulatory roles in cellular function and brain biology. Their closed-loop structure gives them exceptional stability compared to linear RNAs, allowing them to maintain their structural integrity in blood without breaking down quickly.
At Circular Genomics, we are a pioneer in the clinical use of circRNA biomarkers to develop innovative tests that aim to transform the standard of care, making brain disorders measurable, manageable, and more effectively treatable.
circRNAs are highly enriched in the brain and dynamic in their expression, responding to changes in neuronal activity and disease biology. This unique combination of stability and responsiveness provides a real-time view of biological signals which reflect the earliest stages of neurodegeneration.
Our approach:
Bridging brain biology and clinical outcomes
Because circRNAs cross the blood–brain barrier and are readily measurable in the blood, they provide unprecedented access to brain-specific molecular signals. Their expression profiles can be disease-specific and mirror key biological pathways implicated in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other neurodegenerative disorders.
Collectively, these attributes position circRNAs as a biologically rich and clinically actionable foundation for diagnostic innovation and therapeutic discovery in neurodegenerative disease.
Download the Circular RNA whitepaper
Download our whitepaper, Unlocking New Molecular Frameworks of Brain Health, to explore how circular RNA is advancing biomarker precision and targeted interventions in neurological and psychiatric disorders.
Transforming mental health: A new path forward
Tens of millions of patients with psychiatric conditions like major depressive disorder (MDD) and bipolar disorder (BPD) struggle with a "trial-and-error" approach to treatment, which can prolong suffering.⁵ Circular RNAs offer a promising path forward because their levels in the blood are directly linked to the biology of these diseases, providing a real-time window into the brain.
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Nearly 60% of patients with MDD fail to respond to selective serotonin reuptake inhibitor (SSRI) medications, the most common first-line therapy.⁹
In MDD, specific circRNAs can indicate neuroinflammation or predict a patient's response to common antidepressants by linking to serotonin and brain-derived neurotrophic factor (BDNF) receptor activity.
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Our scientists have identified a key circRNA in the blood whose levels are tied to crucial serotonin and BDNF pathways, linking it to known antidepressant response mechanisms.
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In BPD, reduced levels of a neuronal-enriched circRNA, circHOMER1, are associated with cognitive deficits.¹³
The neuronal-enriched circRNA, circHOMER1, is consistently reduced in the prefrontal cortex of BPD patients and is associated with cognitive flexibility deficits.
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Defining a new class of biomarkers for neurological diagnosis and therapeutic discovery
Neurodegenerative diseases share complex and overlapping biology that spans multiple biological pathways, such as inflammation, oxidative stress, synaptic dysfunction, and metabolic dysregulation. CircRNAs capture this complexity by mirroring changes across these interconnected biological pathways, offering a more comprehensive view of disease mechanisms. By quantifying these dynamic molecular signals in the blood, circRNAs provide a non-invasive window into brain biology, supporting early diagnosis, disease monitoring, and accelerated therapeutic discovery.
Alzheimer’s disease (AD)
Alzheimer’s disease is a heterogenous disease driven by multiple interconnected biological pathways that contribute to its onset and progression. CircRNAs represent a novel biomarker class that captures the biology and pathology complexity of the disease. circRNAs enable early and specific detection of Alzheimer’s pathology by capturing molecular changes across multiple key pathways, including neuroinflammation, synaptic function, and tau/amyloid regulation. Through this multi-pathway view of disease biology and pathology, circRNAs provide a strong biological foundation for innovation in Alzheimer’s diagnostics and therapeutic discovery.
circHOMER1 expression is significantly reduced in early AD and correlates with disease severity.⁸
Parkinson’s disease (PD)
circRNAs are emerging as valuable biomarkers in Parkinson’s disease, reflecting molecular alterations that underlie both disease onset and progression. Specific circRNAs, such as circPANK1 and circSNCA, have been linked to α-synuclein aggregation and neurotoxicity, while others, including circEPS15, are associated with neuronal repair and mitochondrial function. By capturing these diverse and interrelated molecular pathways, circRNAs offer potential for early detection, disease monitoring, and therapeutic development in Parkinson’s disease.
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Studies have identified circRNAs as valuable biomarkers in Parkinson's disease onset and progression.
Multiple sclerosis (MS)
In multiple sclerosis, distinct circRNA expression patterns have been identified in blood and central nervous system tissues, highlighting their potential as non-invasive biomarkers of immune and neuroinflammatory activity. Their exceptional stability and disease-specific expression make circRNAs powerful tools for tracking disease activity, evaluating treatment response, and deepening our biological understanding of this complex autoimmune disorder.¹⁸
Studies have identified circRNAs that are expressed differently in
MS patients compared to healthy controls.
circRNA biomarker data:
A dynamic view of treatment response in MDD
Among MDD patients, we observed close to 90% higher baseline (before treatment) blood levels of circular RNA biomarker (circRNAx) in patients who did not respond to sertraline (SERT NR) compared to those who did respond (SERT R) (n=110 patients; p-value <0.0001).*
Identification and validation of circular RNA biomarker
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Dynamic biomarker response to treatment
Significant increases in circular RNA biomarker levels were seen after 8 weeks of sertraline treatment in responders to sertraline (SERT R). This observation indicates that this circular RNA biomarker is responsive to treatment and displays a dynamic expression profile longitudinally.
Performance data
Data from our EMBARC and ANTARES studies showed that MindLight had an overall diagnostic accuracy of 77% for predicting response to SSRI treatment in patients with MDD (PPV=77%, NPV=77%, 1-NPV=23%, ratio between "High Likelihood" and "Low Likelihood" patient response rates = 3.4x; n=101).*
*Response is defined as a 50% or more reduction in HAMD-17 symptom severity following 8 weeks of treatment.
Our pipeline
By harnessing the power of advanced biomarkers, Circular Genomics is developing a pipeline of blood tests that provide predictive insight into critical health outcomes, characterizing a person’s risk for developing neurological and psychiatric diseases and their likelihood of progression. This new standard of care we’re aiming to create is led by our first commercially available product, the MindLight SSRI Antidepressant Response Test. We continue to work on expanding our portfolio based on our circRNA technology platform, including in other brain health conditions with unmet needs, such as Alzheimer’s and Parkinson’s disease.
Related publications
May 1, 2024
A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants
Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs)…
February 17, 2023
Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain
Circular RNAs (circRNAs) are a novel category of covalently-closed non-coding RNAs mainly derived from the back-splicing of exons or introns of protein-coding genes. In addition to their inherent high overall stability, circRNAs, have been shown to have strong functional effects on gene expression via a multitude of transcriptional and post-transcriptional mechanisms...
August 4, 2022
Knockdown of circHomer1 in the orbitofrontal cortex results in differential encoding of salient stimuli
CircHomer1 is an activity-dependent circular RNA (circRNA) isoform produced from back-splicing of the Homer1 transcript. Homer1 isoforms are well-known regulators of homeostatic synaptic plasticity through post-synaptic density scaffold regulation. Homer1 polymorphisms have been associated with psychiatric diseases including schizophrenia (SCZ) and…
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