Table 1 RNA-based therapeutic and vaccine modalities.
From: Breaking the mold with RNA—a “RNAissance” of life science
Type | MoA(s) | Advanced program | Clinical pipeline |
|---|---|---|---|
ASOs | • Single-stranded oligonucleotides1,2,136 • Promote mRNA degradation and target silencing through cleavage of a target RNA sequence using RNase H activity1,2,136 • Use a steric hindrance–based mechanism to alter other functions (e.g., alter splicing of pre-mRNAs to selectively include or exclude certain exons)1,2,136 | Marketed • Nine therapeutics have received approval though two have since been withdrawn101 • First approval in 1998, though this was later withdrawn101 Examples Inotersen (SC): Induces degradation of transthyretin mRNA in the liver to reduce circulating protein levels for the treatment of hereditary transthyretin amyloidosis1,137 Golodirsen (IV) and eteplirsen (IV): Restore mRNA reading frame of dystrophin pre-mRNA to facilitate functional protein production for the treatment of Duchenne muscular dystrophy138,139 Nusinersen (IT): Binds to SMN2 pre-mRNA to promote exon 7 inclusion and increase SMN protein production for treatment of spinal muscular atrophy140 | • At least 50 therapeutics in Phase II or Phase III clinical trials101 • Investigational therapeutics target numerous indications, including metabolic disorders, cancer, and respiratory conditions101 |
siRNAs | • Double-stranded molecules typically 19 to 21 nucleotides long136 • Function as sequence-specific guides to suppress mRNA expression using the endogenous RNAi pathway1,136,38 | Marketed • Four marketed therapeutics and one in preregistration101 • First approval in 2018101 Examples Patisiran (IV): Reduces transthyretin protein production to reduce amyloid deposits for treatment of hereditary transthyretin-mediated amyloidosis1,56 Givosiran (SC): Lowers production of ALA synthase 1 to normalize levels of heme biosynthesis for treatment of acute hepatic porphyria1,54 Inclisiran (SC): Decreases translation of liver PCSK9 to reduce LDL cholesterol levels for treatment of primary hypercholesterolemia or mixed dyslipidemia1,141 | • At least 25 therapeutics in Phase II or Phase III clinical trials101 • Investigational therapeutics target numerous indications, including metabolic disorders, infectious diseases, and cancer101 |
miRNAs | • Endogenous short non-coding RNAs2 • Share the same RNAi machinery as siRNA but can regulate expression of multiple target genes2 • Can be inhibited using ASOs or supplemented for gain-of-function effect2 | Marketed No approved therapeutics to date | • At least 10 therapeutics in Phase I, Phase II, or Phase III clinical trials142 • Investigational therapeutics target different indications, including wound healing, heart failure, T-cell lymphoma, liver cancer, hepatitis, and glioblastoma2,143 |
Aptamers | • Single-stranded oligomers consisting of 20 to 100 bases1,2 • Engineered to bind protein targets based on their tertiary structure to modulate function1,2 • Analogous to the RNA version of monoclonal antibodies2 | Marketed • Two approved therapeutics to date but production has since been discontinued for one of them142 • First approval in 200457 Example Defibrotide (IV): Activates adenosine A1/A2 receptor for treatment of veno-occlusive disease in the liver142 | • At least two therapeutics currently in Phase I or Phase II clinical trials • Investigational therapeutics are currently in development for various indications, including diabetic nephropathy, pancreatic cancer, and glioblastoma/glioma2 |
mRNAs | • Can be used to express any protein, wild-type, or imagined1,53,36 • Rescue or supplement function • Antigen to stimulate an immune response • Effector protein to edit the genome or epigenome • Transcription factor to alter cell state • Chimeric antigen to program the immune system against disease | Marketed • Two approved vaccines142 • Emergency Use Authorization in 2020 Examples Tozinameran (IM) and elasomeran (IM): Elicit translation of a modified spike protein to induce a SARS-CoV-2–specific immune response for the treatment of COVID-192 | • >20 therapeutics and vaccines currently in Phase I, II, or III clinical trials144 • Investigational therapeutics target numerous indications, including infectious diseases and cancer144 |
gRNA/ CRISPR | • Used for gene editing via RNA-guided DNA cleavage then repair at a target DNA site, allowing for specific corrections, alterations, additions, or deletions to the genome145 • Engineering gRNA can improve the system’s specificity, stability, and safety and expand their applications145 | Marketed No approved therapeutics to date | • >25 therapeutics currently in Phase I, II, or III clinical trials21 • Investigational therapeutics target numerous indications, including cancer, sickle cell disease, diabetes, HIV, and hereditary disorders21 |
