Unlocking the potential of circular RNA
SCIENCE
A new window into the brain: Circular RNA
Circular RNAs (circRNAs) are a unique class of non-coding RNA molecules that play a powerful regulatory role in our cells.
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These molecules are particularly abundant in the brain, and their unique, closed-loop structure gives them remarkable stability compared to linear RNAs. This stability, combined with the fact that they are conserved across species, highlights their important biological functions in brain development, maturation, and function.
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Unlike static DNA testing, which reports on a person’s genetic inheritance, circRNAs reflect an individual's current biological state. Because they are highly sensitive to changes in neuronal activity, can cross the blood-brain barrier, and are readily detectable in the blood, their abnormal expression in pathological states positions them as powerful new biomarkers.
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This dynamic quality makes them invaluable for precision neurology and psychiatry.
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.
Our approach:
A direct link to the biology of brain disease
The power of circRNAs lies in their direct mechanistic link to the biology of brain diseases. Generated from genes crucial for synaptic function, they act as "sponges" or "scaffolds" to regulate key cellular processes. When dysregulated, they contribute directly to the molecular dysfunctions behind these conditions. By leveraging these unique properties, Circular Genomics is developing innovative solutions to provide critical insights into disease, paving the way for more personalized and effective patient care.
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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Advancing neurological care: Creating clarity for disease management
To overcome the invasive and subjective methods often used to diagnose neurological disorders,¹⁶ Circular Genomics is pioneering circRNA-based tools that provide a real-time view into brain biology from a simple blood test. This novel approach could potentially enable early screening and disease monitoring for a variety of neurological and psychiatric diseases that are currently under investigation.
Alzheimer’s disease (AD)
circRNAs represent a novel and differentiated class of biomarkers for AD. Unlike static DNA tests that show genetic predisposition, circRNAs provide a dynamic, real-time view of an individual's current brain biology.¹⁷ Because scientific studies confirm these molecules are directly involved in the pathophysiology of AD, they provide a powerful foundation for developing simple blood tests for early diagnosis and disease monitoring.
circHOMER1 expression is significantly reduced in early AD and correlates with disease severity.⁸
Multiple sclerosis (MS)
In this complex autoimmune disorder, differentially expressed circRNAs have been identified in patients.¹⁸
Their stability and specific patterns make them promising biomarkers for non-invasive blood tests to monitor disease activity and treatment effects.
Studies have identified circRNAs that are expressed differently in MS patients compared to healthy controls.
Parkinson’s disease (PD)
For this neurodegenerative disorder, circRNAs are emerging as biomarkers for diagnosis and severity. Some are mechanistically tied to the disease, acting as "sponges" that can increase the aggregation of toxic proteins, while others help promote the recovery of nerve cells.¹⁷
circRNAs like circPANK1 and circSNCA are upregulated in PD models where they act as "sponges" for other molecules, which can lead to increased expression and aggregation of the toxic α-synuclein protein, while another circRNA, circEPS15, is downregulated in PD patients and has been shown to promote the recovery of dopaminergic nerve cells by boosting mitochondrial function.¹⁷
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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