What is GalNAc siRNA?
What is GalNAc siRNA?
GalNAc-siRNA conjugates are a simple solution to the siRNA delivery problem for liver hepatocytes and have shown the RNAi (and antisense oligonucleotide) field the path forward for targeting other tissue types. Keywords: N-acetylgalactosamine; clinical trials; liver.
How does GalNAc work?
GalNAc conjugates bind to the ASGPR and are taken up in endosomes, where the conjugate dissociates from the receptor. Then, the GalNAc sugars and branches are very quickly lysed from the oligonucleotide before the oligonucleotide escapes to the cytoplasm by a still poorly understood mechanism.
How does RNA interference regulate gene expression?
RNAi is short for “RNA interference” and it refers to a phenomenon where small pieces of RNA can shut down protein translation by binding to the messenger RNAs that code for those proteins. RNA interference is a natural process with a role in the regulation of protein synthesis and in immunity.
How does siRNA affect gene expression?
The siRNA-induced post transcriptional gene silencing starts with the assembly of the RNA-induced silencing complex (RISC). The complex silences certain gene expression by cleaving the mRNA molecules coding the target genes. This cleavage results in mRNA fragments that are further degraded by cellular exonucleases.
What does GalNAc stand for?
N-Acetylgalactosamine
N-Acetylgalactosamine (GalNAc), is an amino sugar derivative of galactose.
How does RNA interference result in gene silencing?
RNA interference (RNAi) is a biological mechanism which leads to post transcriptional gene silencing (PTGS) trigger by double stranded RNA (dsRNA) molecules to prevent the expression of specific genes 1, 2.
What is RNA interference?
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is a conserved biological response to double-stranded RNA that mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
How do miRNA and siRNA affect gene expression?
For instance, the siRNA regulates the expression of different genes while the miRNA regulates the expression of similar types of genes or genes having the same origin. Keep in mind that the duo has a direct role in the process of RNA interference but has different effects, targets and modes of action.
How do siRNA molecules silence genes?
In RNAi, small double-stranded RNAs processed from long double-stranded RNAs or from transcripts that form stem-loops, silence gene expression by several mechanisms – by targeting mRNA for degradation, by preventing mRNA translation or by establishing regions of silenced chromatin.
Is galactose and glucose same?
Galactose is a monosaccharide and has the same chemical formula as glucose, i.e., C6H12O6. It is similar to glucose in its structure, differing only in the position of one hydroxyl group. This difference, however, gives galactose different chemical and biochemical properties to glucose.
Which RNA can induce gene silencing?
Explanation: Apart from siRNA, miRNA and piRNA causes gene silencing. The miRNAs or microRNAs are naturally occurring RNAs that direct the repression of genes, but mostly in plants and worms.
What are the preclinical considerations for GalNAc siRNA?
Preclinical considerations • Fate of sense and anti-sense strands • Off-target toxicity • Limited tissue distribution, targeted delivery to liver • Short plasma half-life; long tissue half-life; long PD effects • Metabolized by serum and tissue exo- and endo- nuclease digestion (stability, serum half-life) N-acetylgalactosamine (GalNAc) 6
What are the sugars in O-GalNAc glycans?
The sugars found in O-GalNAc glycans include GalNAc, Gal, GlcNAc, Fuc, and Sia, whereas Man, Glc, or Xyl residues are not represented. Sialic acids may be modified by O-acetylation, and Gal and GlcNAc by sulfation.
Where does GalNAc conjugate bind to liver cells?
GalNAc conjugates – GalNAc, or N-acetylgalactosamine, is a sugar molecule that can recognize and bind to a cell surface protein, the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on liver cells (hepatocytes).
What are three strategic therapeutic areas for Alnylam?
◦Cardiovascular safety ◦Injection site reactions ◦Cytokine responses, complement effects, and immunogenicity ◦Carcinogenicity ◦Clinical translation 3 Alnylam Clinical Development Pipeline Focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious Diseases 4
