Abstract: TH-PO033
Artificial Intelligence Discovers a Novel Antifibrotic Drug for Preventing Chronic Kidney Failure by Targeting Macrophage-Myofibroblast Transition
Session Information
- Augmented Intelligence for Prediction and Image Analysis
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2301 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention
Authors
- Tang, Patrick Ming-Kuen, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Chung, Yat Fai, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Tang, Chiu Tsun Philip, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Chan, Max Kam Kwan, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Wong, Francis Chun Him, Prince of Wales Hospital, Hong Kong, Hong Kong
- Ng, Chi Fai, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Nikolic-Paterson, David J., Monash University, Melbourne, Victoria, Australia
- Lan, Hui Y., The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Tang, Sydney, The University of Hong Kong, Hong Kong, Hong Kong
Background
Kidney failure (end-stage renal disease) is one of the leading causes of death not only in patients with kidney disease but also other non-communicable diseases e.g. diabetes, cardiovascular disease, cancer. Nevertheless, effective treatments to halt the progression of kidney failure remain an unmet clinical need worldwide.
Methods
We recently discovered a novel phenomenon "Macrophage-Myofibroblast Transition" (MMT) as a key pro-fibrotic mechanism and ideal therapeutic target to prevent chronic renal failure. By single-cell RNA sequencing and unbiased bioinformatics analysis, we have identified a neural transcription factor as a key regulator of MMT [Tang et al., PNAS 2020]. Here, by using artificial intelligence (AI) drug discovery platform, we successfully identified a novel anti-fibrotic drug “ISO” for targeting the MMT-driven renal failure.
Results
We found that ISO specifically blocks DNA binding of the neural transcription factor at the molecular level, therefore preventing MMT formation on TGF-β1-stimulated macrophages in vitro. More importantly, by conducting macrophage-specific fate mapping with our unique LyzM-tdTomato transgenic mice, we demonstrated that ISO markedly prevents MMT-driven renal fibrosis induced by unilateral ureteral obstruction (UUO) and renal ischemia/reperfusion injury (IRI) without side effects in vivo.
Conclusion
Thus, our AI-guided novel anti-fibrotic drug ISO may represent a safe and effective MMT-targeted therapy for preventing chronic renal failure in clinics.
Acknowledgements
Health and Medical Research Fund (10210726, 11220576), Passion for Perfection Scheme (PFP202210-004) and CUHK Faculty Innovation Award (4620528).
Funding
- Government Support – Non-U.S.