RNA Based Therapies For Clinical Use

Types Ribonucleic Acid-Based Therapies

Antisense RNAs (single-stranded RNAs)
The Antisense RNA molecules target nucleic acids, either DNA or RNA., and bind to the complementary sequences to the target molecules. After binding, the antisense RNA can modulate the splicing of pre-mRNAs, induce the degradation of target mRNAs mainly through the RNase H-mediated degradation, or block the translation of mRNAs into proteins. e.g. Mipomersin, Nusenursin

Small interfering RNAs (double-stranded RNAs)
The double-stranded siRNA drugs exert their function through the cellular pathway, RNAi. After being loaded into the RNA-induced silencing complex (RISC), the key complex of the RNAi pathway and induces target mRNA degradation. e.g. Givosiran, Inclisiran,

RNA aptamers
The second category of RNA therapy is the RNA drug which targets proteins. This drug includes the RNA aptamer, which binds and modulates the function of proteins. eg. Pegaptanib

Messenger RNAs
The third category of RNA therapy is RNA drugs which are translated into proteins. Thus, mRNA with chemical modifications to increase its stability are used as drugs. After the introduction into the cells, the mRNA is translated into protein and exerts its function. At present, this drug is intended to be used as a personalized cancer vaccine or a vaccine for infectious diseases. e.g COVID vaccine

Delivery Method for RNA Therapies

Nanoparticles
The nanoparticles allow the specific delivery of RNA in the target tissues. In one strategy, RNAs are encapsulated inside the lipid bilayers with a positive surface charge. This lipid nanoparticle protects the RNAs and increases its half-life. Moreover, lipid bilayers increase the efficiency of endocytosis into the cells and help them escape the endosomes. Patisiran is one of the RNA drugs encapsulated inside the lipid nanoparticle. 

RNA conjugates
In this approach, the RNA is covalently attached to the conjugates that bind to the specific receptor on the surface of the cells. This allows the delivery of the covalently bound RNA molecule into a specific cell type. Once the conjugate is bound to the cell surface receptor, the RNA-conjugate complex is introduced into the cells through receptor-mediated endocytosis e.g N-acetylgalactosamine (GalNAc) targets the liver tissue. Givosiran is the first-ever FDA-approved RNA drug based on GalNAc conjugate technology.

Viral Vectors
The efficacy of RNA therapies using viral vectors is being investigated in clinical trials. The adeno associated virus (AAVs) are widely used vectors to deliver DNA and RNA in the target tissues.

FDA/EMA Approved RNA Therapies

Antisense RNA (sense-stranded RNA)

Vitraven (Fomivirsen) for the treatment of CMV retinitis
Kynamro (Mipomersen) for the treatment of Familial Hypocholesterolemia
Spinraza (Nusinersen) for the treatment of Spinal Muscular Atrophy
Exondys 51 (Eteplirsen) for the treatment Duchenne Muscular Dystrophy
Tegsedi (Inotersen) for the treatment of Hereditary Transthyretin Amyloidosis
Vyondys 53 (Golodirsen) Duchenne Muscular Dystrophy

Small Interfering RNA (double-stranded RNA)
Onpattro (Patisiran) for the treatment of Hereditary Transthyretin Amyloidosis
Givlaari (Givosiran) for the treatment of Acute Hepatic Porphyria

OXLUMO (Lumasiran) for the treatment of Primary Hyperoxaluria 1

RNA aptamer
Macugen (Pegaptanib) for the treatment of Age-Related Macular Degeneration

RNA Therapy Focused on Biopharmaceuticals Companies