circRNA Dysfunction Restoration is a novel therapeutic approach that aims to restore levels of neuroprotective circular RNAs (circRNAs) in the aging and neurodegenerative brain. CircRNAs are covalently closed, stable non-coding RNAs that function primarily as microRNA "sponges" and regulators of gene expression. Several neuroprotective circRNAs decline with age and in Alzheimer's disease, Parkinson's disease, and ALS, contributing to synaptic dysfunction and neuronal vulnerability. This therapy uses antisense oligonucleotides (ASOs) or CRISPR-based approaches to restore these protective circRNAs. [@hanan2022] [@kumar2023]
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Overview
Mermaid diagram (expand to render)
circRNA Dysfunction Restoration is a novel therapeutic approach that aims to restore levels of neuroprotective circular RNAs (circRNAs) in the aging and neurodegenerative brain. CircRNAs are covalently closed, stable non-coding RNAs that function primarily as microRNA "sponges" and regulators of gene expression. Several neuroprotective circRNAs decline with age and in Alzheimer's disease, Parkinson's disease, and ALS, contributing to synaptic dysfunction and neuronal vulnerability. This therapy uses antisense oligonucleotides (ASOs) or CRISPR-based approaches to restore these protective circRNAs. [@hanan2022] [@kumar2023]
Circular RNAs (circRNAs) are formed through back-splicing, a process where a downstream 5' splice site connects to an upstream 3' splice site, creating a covalently closed loop structure. This structure makes circRNAs highly stable, resistant to exonuclease degradation, and long-lived in cells—properties that make them attractive as therapeutic targets. [@kristensen2022]
Key neuroprotective circRNAs include:
CDR1as (circRNA-7 / ciRS-7): The most well-characterized circRNA, CDR1as acts as a potent sponge for miR-7, a microRNA that regulates many neuronal genes. CDR1as contains over 70 miR-7 binding sites, sequestering miR-7 and preventing it from repressing target mRNAs involved in synaptic function, neuroprotection, and protein quality control. [@hansen2013]
circSAMD4A: A circRNA that is downregulated in AD brains and regulates synaptic plasticity through miR-138 sequestration. [@dube2019]
circH1PRX: A circular RNA that declines in AD and regulates genes involved in [amyloid-beta](/proteins/amyloid-beta) metabolism. [@zhang2021]
circTLK2: Implicated in PD pathogenesis; regulates neuronal survival through miR-106b binding. [@jin2022]
circSCFD2: Involved in axonal guidance and synaptic function; declines in multiple neurodegenerative conditions. [@ahmad2023]
Why circRNA Restoration?
The "circRNA dysfunction" hypothesis proposes that:
Age-related decline: CircRNA levels naturally decline with age due to reduced back-splicing efficiency and increased degradation
Disease-specific loss: Neurodegenerative diseases accelerate circRNA loss through transcriptional dysregulation
Loss-of-function consequences: Reduced circRNA sponge activity leads to increased microRNA activity, which in turn represses neuroprotective genes
Aggregation susceptibility: Some circRNAs normally bind to and sequester aggregation-prone proteins; their loss may increase aggregation risk
Restoring circRNA levels could:
Re-sequester dysregulated microRNAs
Restore expression of microRNA-targeted neuroprotective genes
Reduce synaptic dysfunction
Potentially interfere with protein aggregation through direct protein binding
Therapeutic Approaches
Approach 1: ASO-Mediated circRNA Upregulation
Design antisense oligonucleotides that bind to the flanking introns of circRNA host genes
The ASO blocks the formation of the linear mRNA splice, shifting splicing toward back-splicing
This increases circRNA production without altering gene transcription
Similar to the nusinersen approach for spinal muscular atrophy [@rigo2014]
CDR1as knockout mice show impaired synaptic transmission and memory deficits [@piwecka2017]
AAV-mediated CDR1as delivery improves cognitive function in 5xFAD mice [@zhang2022]
CDR1as levels are reduced by 40-60% in AD patient brains [@lukiw2018]
miR-7 is upregulated in AD brains and promotes amyloid-beta production [@saugstad2022]
Other circRNAs
circSAMD4A overexpression improves synaptic markers in neuron cultures [@dube2020]
circTLK2 reduction contributes to dopaminergic neuron loss in PD models [@chen2023]
circRNA levels correlate with cognitive performance in aged humans [@grasso2021]
Clinical Evidence
No circRNA-targeted therapies have reached clinical development yet
Several companies (Cardior Pharmaceuticals, Nanosome Therapeutics) are developing circRNA-based cardiovascular therapies, establishing the clinical pathway
Biomarker studies show circRNA levels in blood/CSF may serve as diagnostic or prognostic markers for neurodegeneration [@bhamja2022]
circRNA as Biomarkers
CDR1as can be detected in human CSF and declines in AD [@siegel2021]
Blood circRNA signatures may distinguish AD from PD [@hanan2020]
circRNA profiling may identify patients most likely to respond to restoration therapy
Implementation Roadmap
Preclinical Development (Years 1-4)
Year 1: Target Validation
Confirm circRNA levels in patient-derived [neurons](/entities/neurons) and iPSC models
Validate functional consequences of circRNA loss
Identify optimal circRNA targets
Year 2: Lead Optimization
ASO optimization for CNS delivery
Development of circRNA mimic delivery system
In vivo PK/PD assessment in mouse models
Year 3: Disease Model Testing
Test lead candidates in 5xFAD mice (AD)
Test in [α-synuclein](/proteins/alpha-synuclein) transgenic mice (PD)
Biomarker development for target engagement
Year 4: IND-Enabling Studies
GLP toxicology
Manufacturing development
Regulatory pre-IND meeting
Clinical Development (Years 5-8)
Phase 1 (Year 5): Safety in healthy volunteers
Phase 2 (Year 6-7): Efficacy signal in AD or PD
Phase 3 (Year 8): Registration trial
Commercial Considerations
Market: Large for AD ($10B+), significant for PD
Competitive landscape: No direct competitors in neurodegeneration