From the RNA world to the clinic

Abstract

The study of RNA has continually emphasized the structural and functional versatility of RNA molecules. This versatility has inspired translational and clinical researchers to explore the utility of RNA-based therapeutic agents for a wide variety of medical applications. Several RNA therapeutics, with diverse modes of action, are being evaluated in large late-stage clinical trials, and many more are in early clinical development. Hundreds of patients are enrolled in large trials testing messenger RNAs to combat cancer, small interfering RNAs to treat renal and hepatic disorders, and aptamers to combat ocular and cardiovascular disease. Results from these studies are generating considerable interest among the biomedical community and the public and will be important for the future development of this emerging class of therapeutic agents.

Fig. 1. RNA-based tumor vaccines

A DC-based vaccine is made using tumor antigen, either RNA isolated from a patient’s tumor biopsy or mRNA encoding a known tumor antigen. Patient peripheral blood mononuclear cells are used to isolate CD14⁺ monocytes, which in turn are used to generate immature DCs. RNA is transfected into the patient’s immature DCs, followed by DC activation and maturation ex vivo. These RNA-transfected mature DCs are administered to patients to elicit an antitumor immune response.

Fig. 2. siRNA-mediated treatment of TTR amyloidosis

siRNA-mediated inhibition of mutant TTR synthesis in the liver is used to limit TTR protein generation and subsequent protein misfolding, oligomerization, and systemic pathology. GalNAc (orange triangle) is appended to the siRNA (ALN-TTRSC, black line) to facilitate delivery to hepatocytes through the asialoglycoprotein receptor (ASGPR) and release from the endosomal compartment into the cytoplasm, where the targeting strand (red line) is taken up by the RISC complex. The RISC complex then targets the TTR mRNA (green line; AAA, poly(A) tail) for destruction, preventing synthesis of the TTR protein.

Fig. 3. The factor IXa aptamer anticoagulation system

An anticoagulant aptamer (RB006, blue and green) targeting blood coagulation factor IXa is used to control blood coagulation during percutaneous coronary intervention in patients with acute coronary syndrome (blue bases are the region of aptamer that is recognized by the antidote). Substantial anticoagulation is required to limit clotting during this procedure, in which a catheter is inserted into a peripheral artery and guided to the heart to administer a contrast agent that will indicate sites of blockage in a coronary angiography. If blockage is found in the arteries of a patient’s heart (red circle), angioplasty is often performed to restore blood flow (green circle). To limit bleeding after treatment, the antidote oligonucleotide (RB007, pink) is administered to rapidly unfold the aptamer and restore normal blood hemostasis.