RNA drug delivery
GalNAc
From the pipeline table, it is very clear that the siRNA therapeutics are using more specific GalNac for delivering to the liver.
Dr. Muthiah Mano developed GalNac and received the lifetime achievement award at Oligonucleotide Therapeutics Society (OTS) in 2019. This chemical modification binds to the Asialoglycoprotein receptor that is highly expressed on hepatocytes resulting in rapid endocytosis, thus allowing targeted delivery of GalNac conjugated nucleotide acid drugs to the liver.
Delivery of the RNA drugs remains the biggest challenge for therapeutics, liver target apparently become a lowing hanging fruit with GalNac conjugation. Eyes are another organ that can easily approached through direct injection into fluid inside the eye.
Another hot target for RNA drugs is central nerve system (CNS). This route had proved by the Antisense oligo (ASO) drug Nusinersen that treats the Spinal muscular atrophy (SMA). RNA drugs can not across the blood brain barrier, but they can be intrathecal injected into the spinal cord, and the cerebrospinal fluid circulates the nucleic acid drug throughout the brain, spinal cord and finally reaches the target cells in the brain.
More strategies are also growing to meet the challenge for targeted delivery to other organs, such as nanoparticles, antibody conjugation.
| Drug | Alternative | Company | delivery | Disease |
|---|---|---|---|---|
| Patisiran | ONPATTRO | Alnylam | LNP | Hereditary transthyretin |
| Givosiran | GIVLAARI | Alnylam | GalNAc | Acute hepatic porphyria |
| Lumasiran | ALN-G01 | Alnylam | GalNAc | Primary hyperoxaluria type 1 (PH1) |
| Vutrisiran | ALN-TTRsc02 | Alnylam | GalNAc | Hereditary transthyretin mediated amyloidosis |
| Nedosiran | DCR-PHXC | Dicerna Alnylam | GalNAc | Primary hyperoxaluria |
| lnclisiran | ALN-PCSSC | Alnylam Novartis | GalNAc | Hypercholesterolemia |
| Fitusiran | ALN-AT3sc, ALN-APC, SAR439774 | Alnylam Sanofi Genzyme | GalNAc | Hemophilia A and B |
| Teprasiran | AKli-5, DGFi, l-5NP, QPl-1002 | Quark Novartis | Acute kidney injury Delayed graft function | |
| Cosdosiran | QPl-1007 | Quark | Non-arteritic anterior ischemic optic neuropathy (NAION) | |
| Tivanisiran | SYL-1001 | Sylentis | Dry eyes Ocular pain |