Singapore's Nanyang Technological University (NTU) has unveiled a promising inhaled therapy designed to mitigate lung damage following severe infections. This innovation targets the aftermath of respiratory assaults like influenza, COVID-19, pneumonia, and other pathogens that leave lungs inflamed, fluid-filled, and scarred even after the infection is cleared. Developed over nearly a decade, the treatment could transform recovery for patients worldwide, particularly in regions like Asia where pneumonia ranks high among causes of death.
The therapy addresses acute respiratory distress syndrome (ARDS) and post-infection fibrosis, conditions that prolong hospital stays and impair quality of life. By delivering medication directly to the lungs via inhalation—much like asthma inhalers—it minimizes side effects associated with systemic drugs.
The Persistent Challenge of Lung Damage from Severe Infections
Severe respiratory infections trigger a cascade of immune responses that, while fighting pathogens, often cause collateral damage to lung tissue. Viruses such as H1N1 influenza or bacteria leading to pneumonia disrupt the vascular barrier in the lungs, allowing fluid to leak into air sacs (alveoli). This edema impairs oxygen exchange, leading to hypoxia, while ongoing inflammation promotes fibrosis—scarring that stiffens lung tissue and hinders breathing.
Globally, seasonal influenza impacts up to one billion people yearly, causing 290,000 to 650,000 respiratory deaths. In Singapore, pneumonia is the second leading cause of death after cancer, with over 10,000 hospital admissions annually. Post-COVID, long-term lung complications affect millions, underscoring the need for therapies that not only combat the infection but repair the damage.
Current treatments like corticosteroids reduce inflammation but risk worsening leakage and immunosuppression, especially in bacterial cases. Mechanical ventilation helps acutely but doesn't address root causes of persistent injury.
Unraveling ANGPTL4: The Protein at the Heart of Lung Injury
Angiopoietin-Like 4 (ANGPTL4), full form Angiopoietin-Like Protein 4, emerges as a key culprit. Produced by lung endothelial and epithelial cells under inflammatory stress, ANGPTL4 destabilizes vascular junctions, promoting leakage, edema, and eventual fibrosis. High ANGPTL4 levels correlate with severe outcomes in ARDS patients.
NTU researchers pinpointed ANGPTL4's role through advanced models, revealing how it disrupts tight junctions like VE-cadherin and occludin, allowing plasma proteins and fluid into alveoli. This step-by-step process—pathogen invasion → cytokine storm → ANGPTL4 upregulation → barrier breakdown → edema and fibrosis—highlights a precise intervention point.
How the Inhaled ASO Therapy Works: Precision at the Molecular Level
The NTU-led therapy employs an antisense oligonucleotide (ASO)—a short synthetic DNA-like strand that binds ANGPTL4 messenger RNA (mRNA), triggering its degradation via RNase H. This reduces ANGPTL4 protein production without broad immunosuppression.
Administered via nebulizer, the ASO reaches deep lung regions efficiently, with preclinical data showing 90% retention in lungs and minimal systemic exposure. Unlike pills or IV drugs, inhalation bypasses first-pass metabolism, achieving higher local concentrations safely.
- Step 1: Nebulization aerosolizes ASO for inhalation.
- Step 2: Particles deposit in alveoli, taken up by endothelial/epithelial cells.
- Step 3: ASO hybridizes with ANGPTL4 mRNA.
- Step 4: RNase H cleaves hybrid, silencing gene expression.
- Step 5: Stabilized junctions reduce leakage; inflammation resolves; repair ensues.
This host-directed approach complements antivirals/antibiotics, focusing on tissue protection.
Compelling Preclinical Results: From Mice to Potential Human Impact
In lipopolysaccharide (LPS)-induced bacterial pneumonia mouse models, inhaled ANGPTL4-ASO slashed inflammatory infiltrates, preserved alveolar structure, and lowered edema (reduced wet/dry lung weight ratio). Cytokine levels like IL-6 and TNF-α dropped significantly.
Viral H1N1 (PR8) models showed similar benefits: less vascular leakage, improved survival rates, and better lung compliance. In bleomycin pulmonary fibrosis models, fibrosis markers (hydroxyproline, collagen) decreased, with enhanced lung function.
Large animal (pig) studies confirmed translation: reduced lung injury scores and faster recovery. No toxicity observed; therapy well-tolerated.Advanced Science publication details these outcomes, validating efficacy across infection types.
The NTU Research Powerhouse Behind the Breakthrough
At NTU's Lee Kong Chian School of Medicine (LKCMedicine), Assoc Prof Andrew Tan Nguan Soon, Provost’s Chair in Metabolic Disorders and Vice-Dean (Innovation and Enterprise), co-led the effort. His expertise in RNA therapeutics drove the platform's design.
Co-leader Asst Prof Li Liang from SUSTech brought organoid models for human relevance. NTU team: PhD students Damien Chua and Joseph Kim, Research Associate Liu Yu Xuan, Senior Research Fellow Cheng Hong Sheng—young talents exemplifying NTU's research ecosystem.
Quote from Assoc Prof Tan: “This long-term research programme lays the foundation for RNA-based treatments for lung diseases and supports Singapore’s efforts to strengthen its capabilities in RNA medicine.”
Global Collaborations Elevate Singapore's Research Profile
Partnerships amplify impact: SUSTech provided advanced models; Lipigon Pharmaceuticals supplied the ASO compound (their LPGO-131 platform) and filed a joint patent. Lipigon CEO Johan Liwing: “These findings strengthen our confidence... to advance this RNA therapy into clinical evaluation.”
This trilateral effort—academia-industry-international—mirrors Singapore's biomedical hub strategy, positioning NTU as a leader in respiratory innovation.EurekAlert press release highlights the synergy.
Publication Milestone and Expert Endorsements
Published March 23, 2026, in Advanced Science (DOI: 10.1002/advs.202501909), the study underwent rigorous peer review. Independent experts praise it: Prof David Lye (infectious diseases) sees potential for severe pneumonia survival; Dr Li Guobao notes targeted, low-side-effect benefits for acute lung injury.
Asst Prof Li Liang: “Our approach focuses on precise modulation... progressing into non-human primate evaluation and IND-enabling development.”
Transforming Singapore's Fight Against Respiratory Diseases
Pneumonia's toll in Singapore—10,000+ admissions yearly—demands local solutions. This therapy aligns with national priorities: ageing population, rising chronic lung diseases. NTU's TARIPH (Translational Asian Respiratory Initiative for Patient Health) underpins such work, fostering patient-centric research with Singapore's first respiratory patient panel.
By advancing RNA inhalation tech, NTU bolsters Singapore's mRNA ecosystem, complementing COVID vaccine successes. Potential to cut ICU stays, mortality, and long COVID burdens.
NTU's TARIPH: A Hub for Respiratory Excellence
NTU's TARIPH coordinates multi-institution efforts on Asian lung health, funded by S$10M national grant. Themes: chronic diseases (COPD/asthma), post-ICU care, infections. This inhaled therapy exemplifies TARIPH's translational focus, involving public clusters, med schools.
Recent grants: S$7.4M for lung health, positioning NTU centrally in Singapore's biomedical push.
Advantages Over Existing Treatments
- Targeted: ANGPTL4-specific vs. broad steroids.
- Local Delivery: Inhaled minimizes systemic risks.
- Immune-Sparing: Preserves pathogen fight.
- Multi-Model Efficacy: Bacterial/viral/fibrosis.
Unlike ventilators (invasive) or immunosuppressants (infection risk), it promotes repair.
Path to Clinic: Trials, Patents, and Global Potential
Next: Non-human primate safety, IND filing for Phase 1 trials. Patent protects inhaled platform. Lipigon eyes global development; Singapore's A*STAR/regulators support RNA tech.
Broader: Addresses ageing societies' pneumonia rise (China: 200k deaths/year pre-COVID; Sweden: 2-3k). Could integrate with antimicrobials for combo therapy.
NTU's inhaled ANGPTL4-ASO therapy heralds a new era in respiratory medicine, showcasing Singapore universities' prowess. As trials advance, it promises faster recoveries, fewer complications, and lives saved—exemplifying higher education's role in health innovation. Researchers urge sustained funding for such patient-focused breakthroughs.
For those in academia or medicine, NTU exemplifies how interdisciplinary teams drive impact. Explore opportunities in Singapore's vibrant research scene.
