Therapeutics
Current trends in RNA-based therapeutic development
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.
By Dr Xiaoqiu Wu and Dr Andrew P. Turnbull
R
NA 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 pos- sibility to develop agents against ‘undruggable’ genes and gene products (for a comprehensive review on RNA-targeted therapeutics, please refer to reference 1). 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 unsta- ble 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:
lmRNA vaccines for cancer and infectious disease. l In vitro transcribed (IVT) mRNAs to replace or supplement proteins.
16
l Antisense RNAs, or RNA interference (RNAi) via miRNAs and siRNAs, to partially or complete- ly turn off gene expression. l RNA aptamers, or ‘chemical antibodies’, which bind to specific molecular targets and can act as drug carriers to deliver small-molecule chemother- apeutics, siRNAs, miRNAs or nanoparticles into targeted tissues.
These efforts have led to the therapeutic poten-
tial of RNA drugs being realised2, with the RNA aptamer – pegaptanib (brand name Macugen) – representing the first FDA approval for an RNA- based drug in 2004. Since then, two antisense RNAs – nusinersen (Spinraza) and eteplirsen (Exondys 51) – and one siRNA drug – patisiran (Onpattro) – have gained FDA approval (Table 1). As of July 2018, 69 companies have mRNA, antisense RNA, RNAi or RNA aptamer therapeu- tics in clinical development with 315 ongoing clinical trials (data provided by GlobalData Plc;
https://www.globaldata.com/). Furthermore, sev- eral strategic collaborations and partnerships have been forged between big Pharma and Biotech companies to leverage proprietary tech- nology platforms. For example, Arbutus Biopharma Corporation, which has proprietary LNP and ligand-conjugate delivery technologies, recently entered into an agreement with Roivant Sciences to launch Genevant Sciences. New
Drug Discovery World Fall 2018
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72
