ALN-PCSsc
Introduction to RNAi-based Therapy
RNA interference (RNAi) has shown promising data in inhibiting gene expression in different cell types in humans. Pilot studies have demonstrated that the genes that encode messenger RNA (mRNA) can be degraded into small interfering RNAs (siRNAs) or microRNAs (miRNAs) when double-stranded RNA (dsRNA) sequences are incorporated into the body. Moreover, recent reports have revealed that RNAi-based therapy can be broadly used in the treatment of various human diseases, including cancers, metabolic diseases, neurodegenerative disorders, and viral infections. Recently, various siRNA delivery systems have been generated to deliver target genes to specific tissues rapidly and effectively. For example, a recent study has indicated that lipid-based carriers can be used as suitable components to improve the efficacy of RNAi-based therapy in the clinic. In addition, a novel RNAi-based therapeutic strategy that combines siRNA molecules with antibodies or small molecules has become a key means for treating metabolic diseases and has the potential for clinical use in the further.
Figure 1. Major steps in the RNA interference (RNAi) pathway. (Czech, 2011)
The ALN-PCSsc in Metabolic Disease Treatment
ALN-PCSsc, also known as PCSK9si, is an RNAi therapeutic inhibitor that has been utilized in treating different types of metabolic diseases, such as low-density lipoprotein cholesterol (LDL-C). ALN-PCSsc is designed by covalently linking dsRNA to N-acetylgalactosamine of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in liver cells. Many studies have suggested that gene silencing caused by ALN-PCSsc can significantly reduce the expression level of LDL-C and suppress the function of PCSK9 proteins. For instance, pre-clinical studies conducted on different animal models have indicated that seven months of dosing for ALN-PCSsc enables expression knockdown of 93% PCSK9 and 78% LDL-C. Furthermore, the data have also shown that ALN-PCSsc has a wide range of therapeutic effects and high safety in different species. Besides, ALN-PCSsc has also shown a highly competitive index as compared with antibodies against PCSK9, suggesting it should be candidate LDL-C lowering drugs for various disease therapies.
Nowadays, a series of phase I clinical trials have been conducted to evaluate the safety and toxicity, pharmacokinetics (PK) and pharmacodynamics (PD) property of ALN-PCSsc in patients with elevated LDL-C. Then, a large scale of phase II clinical trials for ALN-PCSsc has been developed for further identification of the data collected from phase I clinical trials. The results have illustrated that ALN-PCSsc plays a critical role in reducing the LDL-C level of up to 82% of patients at a single low dose injection. Additionally, ALN-PCSsc has been considered as a key regulator for mediating atherogenic lipids, such as cholesterol, and it has been broadly used for preventing cardiovascular diseases. Importantly, ALN-PCSsc has proven its vital role in improving the ability of liver clearance in the plasma in patients.
Reference
- Czech, M. P.; et al. (2011). RNAi-based therapeutic strategies for metabolic disease. Nature Reviews Endocrinology. 7(8): 473.
