1 research outputs found
Comprehensive Structure–Activity Relationship of Triantennary <i>N</i>‑Acetylgalactosamine Conjugated Antisense Oligonucleotides for Targeted Delivery to Hepatocytes
The comprehensive structure–activity
relationships of triantennary
GalNAc conjugated ASOs for enhancing potency via ASGR mediated delivery
to hepatocytes is reported. Seventeen GalNAc clusters were assembled
from six distinct scaffolds and attached to ASOs. The resulting ASO
conjugates were evaluated in ASGR binding assays, in primary hepatocytes,
and in mice. Five structurally distinct GalNAc clusters were chosen
for more extensive evaluation using ASOs targeting SRB-1, A1AT, FXI,
TTR, and ApoC III mRNAs. GalNAc–ASO conjugates exhibited excellent
potencies (ED<sub>50</sub> 0.5–2 mg/kg) for reducing the targeted
mRNAs and proteins. This work culminated in the identification of
a simplified tris-based GalNAc cluster (THA-GN3), which can be efficiently
assembled using readily available starting materials and conjugated
to ASOs using a solution phase conjugation strategy. GalNAc–ASO
conjugates thus represent a viable approach for enhancing potency
of ASO drugs in the clinic without adding significant complexity or
cost to existing protocols for manufacturing oligonucleotide drugs