What is the role of non-coding RNAs (ribonucleic acids) in disease management?

Non-Coding RNAs in Disease Management

Non-coding RNAs (ncRNAs) represent the vast majority of the human transcriptome (97-99%) and serve as emerging biomarkers for treatment selection, monitoring therapeutic response, and potentially as therapeutic targets, though most clinical applications remain in early stages with limited evidence for direct impact on mortality and morbidity. 1

Fundamental Biology and Disease Relevance

The human genome transcribes approximately 80% of its sequences, but only 1-3% encode proteins. 1 The remaining transcripts are ncRNAs that have increased in complexity alongside organismal evolution, suggesting fundamental regulatory roles. 1

Key ncRNA categories include:

• MicroRNAs (miRNAs): 19-25 nucleotides in length, regulate gene expression post-transcriptionally, with ~2500 human miRNAs identified targeting >60% of protein-coding genes 1
• Long non-coding RNAs (lncRNAs): >200 nucleotides, involved in chromatin remodeling and gene regulation 1, 2
• Circular RNAs (circRNAs): Closed-loop structures with regulatory functions 1, 3

Clinical Applications in Disease Management

Biomarker Utility for Treatment Decisions

The most clinically relevant application of ncRNAs is as biomarkers to guide cardiovascular therapy, specifically for treatment selection and monitoring ongoing effectiveness. 1

Advantages as biomarkers:

• Stable against degradation in biological fluids with long half-lives 1
• Quantifiable using standard RT-qPCR techniques already available in clinical laboratories 1
• Detectable at low concentrations, similar to peptide biomarkers 1
• Reflect dynamic responses to stressors and environmental factors (diet, exercise, biological rhythms) not captured by traditional markers 1

Specific clinical contexts where ncRNAs show promise:

• Antiplatelet therapy monitoring: Circulating miRNAs (miR-126, miR-191, miR-223) correlate with platelet inhibition and may identify treatment non-responders at higher risk for cardiovascular events 1
• Treatment allocation: ncRNA profiles may reflect the molecular configuration required for therapeutic interventions to be effective 1
• Post-baseline monitoring: Changes in ncRNA signatures can track ongoing treatment effectiveness 1

Therapeutic Targets

Clinical trials have evaluated ncRNA-targeted therapies in chronic hepatitis C (NCT01200420) and kidney disease (NCT02855268), but the majority of investigations remain in pre-clinical stages. 1 Further evidence is needed to demonstrate clinical safety and efficacy for cardiovascular and other diseases before routine therapeutic manipulation can be recommended. 1

Critical Limitations and Caveats

Important practical considerations:

• Only a small percentage of the non-coding transcriptome has been explored for clinical applications 1
• ncRNA expression exhibits high inter-cellular variation and is highly dynamic 1
• Most evidence focuses on diagnosis and prognosis rather than direct impact on mortality, morbidity, or quality of life 1
• The field lacks standardized protocols for measurement and interpretation across different laboratories

Disease contexts beyond cardiovascular:

• Emerging evidence links ncRNA dysregulation to cancer development, metastasis, and cell cycle failures 3, 4, 5
• Neurological and infectious diseases show ncRNA involvement, though therapeutic applications remain investigational 3, 4

Practical Algorithmic Approach

For cardiovascular disease management:

1. Consider ncRNA profiling (particularly miRNAs and lncRNAs) when traditional biomarkers provide incomplete phenotypic characterization 1
2. Use circulating miRNA panels via RT-qPCR for antiplatelet therapy monitoring in patients at high thrombotic risk 1
3. Measure baseline ncRNA signatures before initiating therapy to predict treatment response 1
4. Reassess ncRNA profiles post-treatment to monitor effectiveness and guide dose adjustments 1

The primary pitfall is overestimating current clinical utility: While ncRNAs show biological plausibility and technical feasibility as biomarkers, robust evidence demonstrating improved patient outcomes (reduced mortality, decreased morbidity, enhanced quality of life) compared to standard care remains limited. 1 Most applications should be considered investigational rather than standard practice until larger outcome-based trials are completed.