Kidney Week

Abstract: SA-PO729

RNK288: A MASP2-Targeting Small Interfering RNA (siRNA) for the Treatment of IgA Nephropathy by Blocking the Activation of Lectin Pathway

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Pan, Ling, Rona Therapeutics, Shanghai, --- Select One ---, China

Ling Pan, PhD

• Meng, Guofeng, Rona Therapeutics, Shanghai, --- Select One ---, China

Guofeng Meng, PhD

• Liu, Wei, Keymed Biosciences Inc, Chengdu, Sichuan, China

Wei Liu, APN, MBA, MPH

• Huang, Cong, Rona Therapeutics, Shanghai, --- Select One ---, China

Cong Huang

• Xiaoyan, Yang, Rona Therapeutics, Shanghai, --- Select One ---, China

Yang Xiaoyan, MS

• Cai, Guoqing, Rona Therapeutics, Shanghai, --- Select One ---, China

Guoqing Cai, MSc

• Xu, Xin Xin, Rona Therapeutics, Shanghai, --- Select One ---, China

Xin Xin Xu

• Yue, Ming, Rona Therapeutics, Shanghai, --- Select One ---, China

Ming Yue

• He, Tao, Rona Therapeutics, Shanghai, --- Select One ---, China

Tao He, MSc

• Wang, Lei, Keymed Biosciences Inc, Chengdu, Sichuan, China

Lei Wang, PhD

• Huang, Jinyu, Rona Therapeutics, Shanghai, --- Select One ---, China

Jinyu Huang, PhD

• Fang, Jianwu, Rona Therapeutics, Shanghai, --- Select One ---, China

Jianwu Fang, APN

• Chen, Bo, Keymed Biosciences Inc, Chengdu, Sichuan, China

Bo Chen, PhD

• Shi, Yibin, Rona Therapeutics, Shanghai, --- Select One ---, China

Yibin Shi

Background

IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis, is a major contributor to renal failure, including in young individuals. Accumulating evidence suggests that the overactivation of the lectin pathway critically contributes to the pathogenesis of IgAN. RNK288, a MASP2-targeting siRNA, is developed as a therapeutic agent for IgAN by blocking the activation of the lectin pathway. Here, we demonstrate the efficacy and safety profile of RNK288 in preclinical studies.

Methods

RNK288 was developed by RAZOR^TM platform to achieve an optimized PD and safety profile. The knockdown potencies of RNK288 were evaluated using both in vitro and in vivo models, including primary human hepatocytes (PHH), primary cynomolgus monkey hepatocytes (PCH), humanized MASP2 (hMASP2) transgenic mice and non-human primates (NHP). The safety of RNK288 was investigated by in vitro assay, RNA-seq and repeated-dose toxicity studies in rat and NHP. The efficacy of RNK288 was evaluated in rodent disease models, including grouped ddY mice.

Results

RNK288 suppressed MASP2 expression in PCH and PHH with the half-maximal inhibitory concentrations (IC₅₀) of 0.02nM and 0.03nM, respectively. In hMASP2 mice, RNK288 reduced serum MASP2 protein by up to 94% after a single subcutaneous injection of 3 mg/kg. In NHP, a single dose of RNK288 significantly lowered MASP2 protein levels to 3.8% even after 3 months, indicating a robust and long-lasting efficacy. In addition, the activity of lectin pathway, was shown to be reduced to a minimum of 13% of the pre-dose level. In repeated-dose toxicity studies (Q2W, 3 doses), no adverse findings were observed in either rats or monkeys and the No Observed Adverse Effect Levels (NOAEL) were 300 mg/kg (the highest dose) for both species. RNA-seq and in silico analysis also indicated low off-target risk, confirming the good safety profile of RNK288. Moreover, RNK288 demonstrated signs of IgAN improvement in rodent disease models.

Conclusion

RNK288 is a novel siRNA drug candidate for the treatment of IgAN by blocking the activation of lectin pathway. A series of preclinical studies demonstrated the robust and long-lasting efficacy of RNK288 with good safety and tolerability. RNK288 represents a potential therapeutic option for patients with IgAN.

Funding

• Commercial Support – RONA Therapeutics