5 research outputs found
G-quadruplex nanoestructure with N-acetilgalactosamine as potential enhancer for oligonucleotide drug delivery
No full textsiRNA Conjugates Carrying Sequentially Assembled Trivalent <i>N-</i>Acetylgalactosamine Linked Through Nucleosides Elicit Robust Gene Silencing <i>In Vivo</i> in Hepatocytes
No full textAsialoglycoprotein
receptor (ASGPR) mediated delivery of triantennary <i>N</i>-acetylgalactosamine (GalNAc) conjugated short interfering
RNAs (siRNAs) to hepatocytes is a promising paradigm for RNAi therapeutics.
Robust and durable gene silencing upon subcutaneous administration
at therapeutically acceptable dose levels resulted in the advancement
of GalNAc-conjugated oligonucleotide-based drugs into preclinical
and clinical developments. To systematically evaluate the effect of
display and positioning of the GalNAc moiety within the siRNA duplex
on ASGPR binding and RNAi activity, nucleotides carrying monovalent
GalNAc were designed. Evaluation of clustered and dispersed incorporation
of GalNAc units to the sense (S) strand indicated that sugar proximity
is critical for ASGPR recognition, and location of the clustered ligand
impacts the intrinsic potency of the siRNA. An array of nucleosidic
GalNAc monomers resembling a trivalent ligand at or near the 3′
end of the S strand retained <i>in vitro</i> and <i>in vivo</i> siRNA activity, similar to the parent conjugate
design. This work demonstrates the utility of simple, nucleotide-based,
cost-effective siRNA–GalNAc conjugation strategies
A rapid two-step method for isolation of functional primary mouse hepatocytes: cell characterization and asialoglycoprotein receptor based assay development
No full textsiRNA Conjugates Carrying Sequentially Assembled Trivalent <i>N-</i>Acetylgalactosamine Linked Through Nucleosides Elicit Robust Gene Silencing <i>In Vivo</i> in Hepatocytes
No full textAsialoglycoprotein
receptor (ASGPR) mediated delivery of triantennary <i>N</i>-acetylgalactosamine (GalNAc) conjugated short interfering
RNAs (siRNAs) to hepatocytes is a promising paradigm for RNAi therapeutics.
Robust and durable gene silencing upon subcutaneous administration
at therapeutically acceptable dose levels resulted in the advancement
of GalNAc-conjugated oligonucleotide-based drugs into preclinical
and clinical developments. To systematically evaluate the effect of
display and positioning of the GalNAc moiety within the siRNA duplex
on ASGPR binding and RNAi activity, nucleotides carrying monovalent
GalNAc were designed. Evaluation of clustered and dispersed incorporation
of GalNAc units to the sense (S) strand indicated that sugar proximity
is critical for ASGPR recognition, and location of the clustered ligand
impacts the intrinsic potency of the siRNA. An array of nucleosidic
GalNAc monomers resembling a trivalent ligand at or near the 3′
end of the S strand retained <i>in vitro</i> and <i>in vivo</i> siRNA activity, similar to the parent conjugate
design. This work demonstrates the utility of simple, nucleotide-based,
cost-effective siRNA–GalNAc conjugation strategies
