Aptamer targeting HMGB1 attenuates inflammatory disease via domain-specific antagonism.
Summary
ZH-1a, a DNA aptamer with nanomolar affinity to the HMGB1 B-box, neutralized extracellular HMGB1, dampened inflammatory signaling, and improved survival in polymicrobial sepsis. The aptamer also reduced late-phase systemic inflammation and organ injury across multiple in vivo models, supporting HMGB1 neutralization as a therapeutic strategy.
Key Findings
- Identified ZH-1a, a DNA aptamer (Kd = 2.1 nM) that preferentially binds the HMGB1 B-box.
- ZH-1a suppressed HMGB1-induced cytokine release and NF-κB activation in macrophages.
- In vivo, ZH-1a reduced late-phase systemic inflammation, improved survival in polymicrobial sepsis, and mitigated multiorgan injury.
Clinical Implications
If translated, HMGB1-neutralizing aptamers could complement antibiotics and source control by suppressing damaging late-phase inflammation, potentially benefiting patients with persistent systemic inflammation or organ failure after initial resuscitation.
Why It Matters
Provides domain-specific biologic antagonism against a late mediator of sepsis with survival benefit, representing a potentially paradigm-shifting immunomodulatory approach. The study integrates target validation with therapeutic proof-of-concept across models.
Limitations
- Preclinical models; human pharmacokinetics, immunogenicity, and safety are unknown.
- HMGB1 pleiotropy and timing of intervention may affect therapeutic windows and generalizability.
Future Directions
Optimize aptamer stability and delivery, perform large-animal sepsis studies, define pharmacodynamics/biomarkers for patient selection, and initiate phase I trials possibly in combination with standard sepsis care.
Study Information
- Study Type
- Case series
- Research Domain
- Treatment
- Evidence Level
- V - Preclinical mechanistic/therapeutic studies in animal models and cells
- Study Design
- OTHER