Singapore’s Nanyang Technological University (NTU Singapore), in collaboration with China’s Southern University of Science and Technology (SUSTech) and Swedish biotech company Lipigon Pharmaceuticals AB, is working to develop a new inhaled treatment aimed at helping patients recover faster from serious lung infections.
This treatment aims to reduce excessive inflammation in the lungs that can persist even after viruses and bacteria have been cleared from the body.
Infectious diseases such as seasonal influenza, Covid-19, Severe Acute Respiratory Syndrome (SARS), avian influenza, and pneumonia trigger the body’s immune system to fight invading pathogens. However, in some patients, this immune response becomes too strong.
When this happens, the lungs become inflamed and fluid can leak from small blood vessels into the air sacs, flooding them. This makes breathing very difficult and reduces the amount of oxygen reaching the bloodstream. The damage may also persist for days or even weeks after the infection has subsided, and patients may feel short of breath.
In severe cases, patients develop acute respiratory distress syndrome. This is a life-threatening condition characterized by widespread lung inflammation and fluid accumulation.
To address this, new treatments target a protein called angiopoietin-like protein 4 (ANGPTL4), which increases during inflammatory stress in the lungs. High levels of ANGPTL4 are associated with increased vascular permeability and fibrosis in injured lung tissue.
The treatment is delivered directly to the lungs by inhalation, similar to how asthma medications are administered, rather than as a pill or injection. This allows it to work where it is needed most while limiting its impact on other parts of the body.
In a preclinical study jointly led by NTU Singapore and SUSTech, inhaled treatment reduced lung inflammation and fluid accumulation in models of bacterial pneumonia and viral influenza.
In experiments, it also reduced lung scarring and improved breathing in models of pulmonary fibrosis, a chronic disease in which the lungs become stiff.
“Severe lung infections often cause lung damage caused by an exaggerated host inflammatory response,” explained SUSTech’s Associate Professor Li Liang, co-leader of the study.
“Our approach focuses on precisely modulating defined molecular targets to maintain lung integrity while maintaining essential immune defenses. Following robust preclinical validation across infection and fibrosis models, this program is progressing to development that will enable non-human primate evaluation and investigational new drug (IND) as the next step in clinical translation.” said Associate Professor Lee, an expert on human organoids and respiratory diseases.
NTU Associate Professor Andrew Tan, co-leader of the study and Chair of Metabolic Diseases at Lee Kong Chian College of Medicine (LKCMedicine), said the research took nearly a decade and represents an important step towards more targeted treatments for lung injury.
“This long-term research program will lay the foundation for RNA-based treatments for lung diseases and support Singapore’s efforts to strengthen its capacity in RNA medicine,” said Associate Professor Tan, who is also Deputy Dean (Innovation and Enterprise) at LKCMedicine. “By identifying and validating pulmonary targets that can be treated by inhalation, we are helping to position Singapore in the emerging field of RNA therapy for respiratory diseases.”
Global and regional burden of lung infections
Severe lung infections remain a major global health challenge. It is estimated that seasonal influenza alone affects up to 1 billion people each year, causes 3 million to 5 million people to become seriously ill, and causes 290,000 to 650,000 deaths annually from respiratory complications.
Furthermore, pneumonia and other lower respiratory tract infections are one of the leading causes of death worldwide, claiming millions of lives each year and placing a huge burden on healthcare systems.
Pneumonia ranks as the leading cause of death in Singapore, accounting for a significant portion of deaths in recent years, second only to cancer.
More than 10,000 people are hospitalized with pneumonia each year, making it one of the leading causes of hospitalization.
Before the Covid-19 pandemic, lower respiratory tract infections such as pneumonia and influenza-related complications were estimated to cause 190,000 to 220,000 deaths annually in China.
In Sweden, there are approximately 2,000 to 3,000 deaths per year from pneumonia and other lower respiratory tract infections, but seasonal influenza causes an estimated 300 to 1,000 excess deaths, mainly among the elderly.
Although improved access to health care has reduced mortality rates over the past two decades, the absolute burden remains high given the aging populations of all three countries.
Professor David Lai, a senior consultant at the National Center for Infectious Diseases and clinical co-director of the Respiratory and Infectious Diseases Program at the Lee Kong Chian Medical School, said in an independent comment: “Corticosteroids are effective in reducing mortality in severe COVID-19 pneumonia, but the evidence for corticosteroids in bacterial pneumonia and influenza is less convincing. Although the current findings are preclinical, none of the new clinically proven treatments are effective.” The ability to reduce lung inflammation as a result of a patient’s immune response to infectious agents is good news in improving survival rates in severe pneumonia. ”
Dr. Li Guobao, director of the Third Department of Pulmonary Diseases at Shenzhen Third People’s Hospital, also commented independently: “Inhalation therapy may provide a targeted and patient-friendly treatment option.”
“ANGPTL4 antisense therapy is administered by inhalation and can act directly on the lungs while minimizing exposure to other parts of the body. This supports a favorable safety profile with fewer side effects,” he said. “It is non-invasive and easy to use, which may improve patient compliance. The treatment works by reducing inflammation, repairing the lung barrier, and reducing scarring, providing a safer and better-tolerated option for conditions such as acute lung injury, severe pneumonia, and pulmonary fibrosis.”
Research studies conducted using Lipigon compounds
Lipigon Pharmaceuticals AB provided the compounds used in the study and is working with NTU and SUSTech on translational development, which will help pave the way for future treatments.
We are encouraged by these new preclinical data, which further strengthen the body of evidence supporting the potential of RNA-based therapies to protect lung tissue in severe lung disease. Severe lung diseases represent a substantial and largely unmet global medical need, and developing innovative treatments that make a meaningful difference for patients facing these life-altering conditions is our top priority. These findings strengthen our confidence in the biological rationale of this approach and support our ambition to advance this RNA therapy to clinical evaluation. ”
Johan Liwing, Lipigon Pharmaceuticals AB CEO
Early safety studies showed that when administered by inhalation, the majority of the therapeutic remains in the lungs, with minimal distribution to other organs. This localized approach may allow for higher concentrations at the site of injury while limiting potential side effects elsewhere in the body.
With support from the NTU Innovation and Entrepreneurship Initiative, a joint patent covering an inhalation therapy platform has been filed by the partners. They are currently conducting further research to support regulatory requirements and future clinical trials.
If developed and approved, this inhaled therapy could provide a new treatment option to limit lung damage and reduce long-term complications in patients recovering from severe respiratory infections.
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Nanyang Technological University, Singapore
