Kidney Week

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

Patrick Ming-Kuen Tang, PhD

• Chung, Yat Fai, The Chinese University of Hong Kong, Hong Kong, Hong Kong

Yat Fai Chung, PhD

• Tang, Chiu Tsun Philip, The Chinese University of Hong Kong, Hong Kong, Hong Kong

Chiu Tsun Philip Tang, PhD

• Chan, Max Kam Kwan, The Chinese University of Hong Kong, Hong Kong, Hong Kong

Max Kam Kwan Chan, PhD

• Wong, Francis Chun Him, Prince of Wales Hospital, Hong Kong, Hong Kong

Francis Chun Him Wong, MBBS

• Ng, Chi Fai, The Chinese University of Hong Kong, Hong Kong, Hong Kong

Chi Fai Ng, MD

• Nikolic-Paterson, David J., Monash University, Melbourne, Victoria, Australia

David J. Nikolic-Paterson, PhD, FASN

• Lan, Hui Y., The Chinese University of Hong Kong, Hong Kong, Hong Kong

Hui Y. Lan, MD, PhD

• Tang, Sydney, The University of Hong Kong, Hong Kong, Hong Kong

Sydney Tang, MD, MBBS, PhD

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.