Study unveils LEF1-AS1 as a promising therapeutic target for rheumatoid arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disease that causes inflammation. It is characterized by synovial hyperplasia. Maintaining an equilibrium between the growth and death of rheumatoid arthritis synovial fibroblasts (RASFs) is vital to prevent damage to bones and cartilage and ultimately slow down the progression of RA. A recent study published in Arthritis Research and Therapy highlights LEF1-AS1 as a potential target for RA treatment.  

Zhang and the team at Bengbu Medical College, China conducted the study involving 24 patients diagnosed with RA. The participants underwent synovectomy, and tissue samples were obtained during joint surgery for analysis. The study focused on assessing the expression levels of LEF1-AS1, miR-30-5p, PIK3R2, p-PI3K, and p-AKT in primary RASFs (rheumatoid arthritis synovial fibroblasts) and a cell line resembling human fibroblast-like synovial cells (HFLS). Furthermore, the researchers utilized Zn-Adenine nanoparticles (NPs) modified with an anti-CD305 antibody to create (Zn-Adenine)@Ab. 

 Subsequently, these NPs were infused specifically with LEF1-AS1, resulting in the creation of (Zn-Adenine)@Ab@lncRNA LEF1-AS1. In the final step, researchers localized the injection of these specialized (Zn-Adenine)@Ab@lncRNA LEF1-AS1 nanoparticles into a rat model exhibiting collagen-induced arthritis (CIA) as part of the experimental procedure. The primary RASFs displayed a notably low expression of LEF1-AS1, while the HFLS cells exhibited substantially higher levels of LEF1-AS1, correlating with a marked decrease in miR-30-5p. Remarkably, the (Zn-Adenine)@Ab@lncRNA LEF1-AS1 nanoparticles demonstrated a significant ability to impede the proliferation of RASFs and reduce the production of inflammatory cytokines (such as IL-1β, IL-6, TNF-α). When administered via intra-articular injection (IAI) into rats modeled with CIA, these (Zn-Adenine)@Ab@lncRNA LEF1-AS1 nanoparticles significantly reduced both cartilage degradation and joint injury. 

 The inflammatory process in RA is regulated by the PI3K/AKT signaling pathway. Inhibiting this signal has been shown to reduce the production of pro-inflammatory mediators, increase anti-inflammatory cytokine levels, and alleviate synovial inflammation in RA patients. The PI3K/AKT pathway is influenced by lncRNAs, playing a vital role in gene expression regulation. Certain lncRNA-miRNA regulatory networks have been identified as crucial in the development of RA, linked to abnormal differentiation and proliferation of rheumatoid synovial cells. 

In the present study, researchers successfully engineered a novel nano-drug, (Zn-Adenine)@Ab@lncRNA LEF1-AS1, designed specifically for treating RA. This innovative drug was created by modifying the Zn-Adenine metal organic framework with an anti-CD305 antibody and incorporating LEF1-AS1. Notably, this drug delivery system not only increased the rate at which regulatory factors were absorbed into cells but also achieved precise, localized therapy for RA. Functioning at a molecular level, LEF1-AS1 played a pivotal role in regulating the development of RA by targeting the miR-30-5p/PIK3R2 axis. The findings suggest that these nanoparticles hold significant potential as carriers for delivering therapeutic molecules directly to targeted sites for the treatment of RA. 


Zhang X, He X, Zhang M, Wu T, Liu X, Zhang Y, et al. Efficient delivery of the lncRNA LEF1-AS1 through the antibody LAIR-1 (CD305)-modified Zn-Adenine targets articular inflammation to enhance the treatment of rheumatoid arthritis. Arthritis Res Ther. 2023 Dec 7;25(1):238.  





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