siRNA-based Therapeutics for Metabolic Diseases
Introduction to siRNA-based Therapeutics
Small interfering RNA (siRNA) is a type of non-coding RNA (ncRNA) that plays an important role in mediating the functions of gene, RNA, and protein. In the past few years, siRNAs have been considered as essential mediators of RNA interference (RNAi) ranging in length from 21 to 23 base pairs. Meanwhile, pilot studies have indicated that siRNAs are capable of reducing and silencing the expression of target genes in a sequence-specific manner. As a result, siRNAs have been broadly used as powerful tools for analyzing the function of single genes.
Furthermore, many reports have shown that siRNAs can also be used for developing promising new therapies for a wide variety of human diseases, especially for metabolic diseases. However, the delivery of siRNAs to target cells or tissues is still a major barrier that can seriously affect the efficacy of siRNA-based therapeutics both in preclinical and clinical use. Many efforts have been made recently to generate safe and effective delivery systems to transmit sequence-specific siRNA to target cells or tissues. For instance, a group of siRNA delivery platforms, including liposome, polyplexes, liposome-polycation-DNA (LPD) complexes, and siRNA conjugates, have been designed for the treatment of metabolic diseases. The results have illustrated that 58-80% have been observed to induce gene silencing with high efficiency in various metabolic disease models.
Figure 1. miRNA pathway and RNAi in cells targeted by small RNA-based therapies. (Lares, 2010)
The siRNA-based Metabolic Disease Treatment
siRNAs, which can inhibit gene expression mediated by sequence complementarity, have been utilized as an attractive tool for treating a wide spectrum of metabolic disorders, including hypercholesterolemia. Nowadays, a series of therapeutic drugs targeting different types of genes, such as the gene proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein B (ApoB), have been developed and tested both in preclinical and clinical trials. For example, ALN-PCSsc is utilized as an RNAi therapeutic inhibitor for treating elevated low-density lipoprotein cholesterol (LDL-C). PRO-040201 and ALN-PCS02 are regarded as RNAi-based drugs for the treatment of high-density lipoprotein cholesterol (HDL-C).
In recent years, a range of clinical trials has been conducted by many companies and organizations to determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single dose and multiple doses of candidate drugs in healthy volunteers and subjects with specific diseases. In general, a placebo-controlled, single/double-blind study will be designed and performed for a long period. The data derived from phase I/II have suggested that most siRNA therapeutic drugs can represent effective and durable gene silencing in tissues, promising clinical outcomes and high safety and little toxicity.
Reference
- Lares, M. R.; et al. (2010). RNAi and small interfering RNAs in human disease therapeutic applications. Trends in biotechnology. 28(11): 570-579.
