RNA Therapeutics Flashcards
Main differences between small molecule drugs and macromolecular drugs
→ Small molecule drugs have a lower mw, are more stable, are less immunogenic, are more easily purified, manufacture is readily scaled up, have simpler structures, and are often amenable to oral admin
Approved ASOs in the EU
Spinraza, Waylivra
5 siRNA drugs approved
Patisiran, Givosiran, Inclisiran, Lumasiran, Vutrisiran
Challenges for pharmaceutical use of nucleic acids?
- Safe & effective delivery to correct target (polyanions, large size, inability to enter cells on their own)
- Delivery systems capable of targeting tissues beyond the liver
- Pre-existing immunity (e.g. anti-PEG Abs, viral vectors)
- Control over dose & duration of therapeutic effect
- Limited admin (low oral bioavailability)
- Shelf-life stability & price
Chemical modifications can protect nucleic acid-based therapies against…
host immunogenic responses to RNA
What are siRNAs?
short dsRNAs (21-25 nt), 2 nt overhangs at 3’ ends
generated from long dsRNA fragments or chemically synthesised
siRNAs efficiently load mRNAs onto __ , which leads to mRNA cleavage
RISC complex
Advantage of siRNAs
They have near perfect complementarity with the target sequence - very specific, less immunogenic
The first non-viral siRNA medicine to reach the market
Patisiran (Onpattro)
Patisiran
siRNA-LNP approved for Transthyrin (TTR) amyloidosis
Patisiran is a very effective way to…
reduce serum levels of misfolded amyloid protein
What are a simple solution to the siRNA delivery problem for hepatocytes?
GalNAc-siRNA conjugates
N-acetyl galactosamine (GalNAc) has a high affinity for the __
asialoglycoprotein receptor (ASGPR) expressed on hepatocytes
GalNAc-siRNA conjugates allow for…
s.c. admin & less frequent dosing
What is Givosiran (Givlaari)?
FDA approved for adults with acute hepatic porphyria
→ GalNAc-siRNA conjugate that targets aminolaevulinic acid synthase 1 (ALAS1) mRNA to reduce toxic metabolites