Researchers in Singapore and the United States have developed a new AI-driven approach to identify gender-specific drug combinations for treating aortic valve stenosis (AVS), a serious heart condition that disproportionately affects older adults. The study highlights the importance of personalised medicine and the need to consider biological differences between men and women when developing treatments.
Targeting AVS with precision
AVS affects around one in eight adults over the age of 75 worldwide. The condition is caused by the narrowing or stiffening of the aortic valve, which restricts blood flow from the heart to the rest of the body. If left untreated, AVS can lead to heart failure. Symptoms may include chest pain, fatigue, breathlessness, and fainting.
Despite the severity of AVS, most clinical drug trials and treatments have historically been based on male patients, resulting in limited efficacy for women. To address this, researchers from the Institute for Digital Medicine (WisDM) at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), Cancer Science Institute of Singapore, and the University of California San Diego have used artificial intelligence to develop gender-specific drug combinations.
Using the IDentif.AI platform, the team optimised combinations of drugs to inhibit myofibroblast activation—one of the key biological processes involved in AVS—based on male and female heart valve cells derived from laboratory models.
AI-generated drug combinations show gender-dependent effectiveness
The AI tool identified drug combinations that were more effective in either male or female valve cells. For example, the combination of Y-27632, SB-203580 and SD-208 showed better results in female cells, while LY294002, Irosustat and TM5441 worked more effectively in male cells. Most of the drugs used in the study are still in the preclinical or investigational stages, with the exception of Losartan, a commonly prescribed drug for hypertension.
Interestingly, the top-performing combinations included Losartan, suggesting that combining approved drugs with new investigational compounds may speed up the development and approval of new treatment options for AVS. Previous large-scale clinical trials for AVS drugs have struggled to deliver results, largely due to the failure to account for gender-based biological differences.
The findings could also offer alternatives to the current standard of care for AVS, which typically involves surgical or transcatheter aortic valve replacement. By providing a clearer understanding of how men and women respond differently to treatment, the study paves the way for more tailored therapies for AVS and potentially other diseases.
Insights from collaborative research
The research, published in Science Advances, involved testing 59 drug combinations across at least 12 samples of male and female valvular interstitial cells (VICs). These cells were cultured in hydrogel biomaterials that closely replicated the environment and stiffness of human heart valves. The team assessed the effectiveness of the drug combinations by measuring their ability to inhibit myofibroblast activation, a process linked to valve stiffening and scarring.
Professor Dean Ho, Director of WisDM at NUS Medicine and co-leader of the study, said, “Our collaborative study demonstrates that men and women may require different medications or drug combinations to achieve the best outcomes in diseases like AVS. By optimising AI and hydrogel biomaterials, we can quickly identify and validate personalised therapies that consider these key differences.”
Professor Brian Aguado, co-leader of the study from the Shu Chien-Gene Lay Department of Bioengineering at the University of California San Diego, added, “The hydrogel biomaterials developed in our laboratory enabled the discovery that male and female VICs have sex-dependent synergistic responses to drug combinations. Our observations would not have been possible using conventional tissue culture plastic materials.”
Dr Peter Wang, co-author of the study from WisDM and the NUS N.1 Institute for Health, noted, “With the findings from our study, we aim to accelerate the development of sex-specific drug combinations for diseases like AVS and emphasise the importance of considering sex as a biological variable in treatment design.”
The team now plans to build on this work by using hydrogel biomaterials and AI-driven platforms to explore treatments for other diseases that display gender-specific responses. The approach may help redefine how clinical trials are designed and accelerate the move towards more precise, personalised care.
