RNAi therapeutics: a potential new class of pharmaceutical drugs

Abstract

The rapid identification of highly specific and potent drug candidates continues to be a substantial challenge with traditional pharmaceutical approaches. Moreover, many targets have proven to be intractable to traditional small-molecule and protein approaches. Therapeutics based on RNA interference (RNAi) offer a powerful method for rapidly identifying specific and potent inhibitors of disease targets from all molecular classes. Numerous proof-of-concept studies in animal models of human disease demonstrate the broad potential application of RNAi therapeutics. The major challenge for successful drug development is identifying delivery strategies that can be translated to the clinic. With advances in this area and the commencement of multiple clinical trials with RNAi therapeutic candidates, a transformation in modern medicine may soon be realized.

Figure 1. Cellular mechanism of RNA interference.

Long double-stranded RNA (dsRNA) is cleaved, by the enzyme Dicer, into small interfering RNA (siRNA). These siRNAs are incorporated into the RNA-induced silencing complex (RISC), where the strands are separated. The RISC containing the guide or antisense strand seeks out and binds to complementary mRNA sequences. These mRNA sequences are then cleaved by Argonaute, the enzyme within the RISC responsible for mRNA degradation, which leads to mRNA down-modulation. A, adenosine.

Figure 2. Chemical modifications of siRNAs.

Shown are structures of sugar, backbone and base modifications and of the cholesterol conjugate.

Figure 3. Critical nucleotide positions in siRNAs.

Nucleotides that are important for potency, mRNA recognition, mRNA cleavage and cleavage specificity, including minimization of off-targeting, are shown.

Figure 4. Organs for which RNAi proof of concept has been demonstrated.

Direct RNAi represents local delivery of RNAi, and has been carried out successfully to specific tissues or organs, including lung, eye, the nervous system, tumors, the digestive system and vagina. Systemic RNAi represents intravenous delivery of RNAi and has been carried out successfully to lung, tumors, liver and joint. Specific disease models are indicated where efficacy was achieved.