Cellular RNAs play crucial roles during disease progression and represent a diverse and largely untapped class of biomolecules that can be exploited for drug development.
RNA species include messenger RNAs (mRNAs) that are translated into proteins, long non-coding RNAs including transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), and small non-coding RNAs such as micro RNAs (miRNAs) and small interfering RNAs (siRNAs).
Exploiting RNA species as therapeutic agents offers new opportunities for drug developers, and the possibility to develop agents against ‘undruggable’ genes and gene products.
Furthermore, new screening tools now make it easier to target disease-associated RNA sequences. However, developing RNA-based therapeutics is not without its challenges since RNA is inherently unstable and prone to degradation by active and abundant ribonucleases (RNases), is potentially immunogenic and may require a delivery vehicle for efficient and specific transport to target cells and across the lipid bilayer.
These development hurdles have largely been overcome by chemically modifying RNA to enhance its stability, and by employing synthetic carriers such as lipid nanoparticle (LNP) or polymer-based nanoparticle (PNP) systems for RNA drug delivery.
RNA drug development efforts have primarily focused on four modalities:
-mRNA vaccines for cancer and infectious disease.
-In vitro transcribed (IVT) mRNAs to replace or supplement proteins.
-Antisense RNAs, or RNA interference (RNAi) via miRNAs and siRNAs, to partially or completely turn off gene expression.
-RNA aptamers, or ‘chemical antibodies’, which bind to specific molecular targets and can act as drug carriers to deliver small-molecule chemotherapeutics, siRNAs, miRNAs or nanoparticles into targeted tissues.
These efforts have led to the therapeutic potential of RNA drugs being realised (2), with the RNA aptamer – pegaptanib (brand name Macugen) – representing the first FDA approval for an RNAbased drug in 2004. Since then, two antisense RNAs – nusinersen (Spinraza) and eteplirsen (Exondys 51) – and one siRNA drug – patisiran (Onpattro) – have gained FDA approval.
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