The U1 Adaptor concept. 
U1 snRNP is a canonical pre-mRNA splicing factor that recognizes the 5’ splice site (5’ss) through base pairing between the U1 snRNA 5’ end and the 5’ss sequence.  Aside from its function in splicing, U1 snRNP is also able to inhibit expression of specific genes by base pairing to the last exon (the 3’ terminal exon) of the pre-mRNA, leading to inhibition of the polyA site.  Without an active polyA site the gene-specific pre-mRNA fails to mature and is degraded in the nucleus.  The U1 Adaptor method exploits this natural ability of U1 snRNA/U1 snRNP to inhibit gene-specific polyA site activity. As shown below, a U1 Adaptor is a synthetic oligonucleotide (~28-33 nucleotides) comprised of a 5’ segment, the Target Domain, which binds within the terminal exon of the target pre-mRNA, and a 3’ segment, the U1 Domain, which binds to the 5’ end of U1 snRNA.  A U1 Adaptor tethers the U1 snRNA subunit of U1 snRNP to a sequence (the target sequence) near the polyA site of the target gene.  The U1 Domain is common to all U1 Adaptors and is simply designed to base pair as strongly as possible to the U1 snRNA.  In contrast, the Target Domain design is a balance between high affinity to the target sequence of the target gene and low affinity to non-targeted pre-mRNAs.   Silagene has validated a target site selection algorithm for identification of potent U1 Adaptors.

Advantages over other methods.
As their inhibitory mechanism does not require enzymatic activity, U1 Adaptor oligonucleotides can withstand up to 100% modification of their backbone and covalent attachment of delivery groups (e.g. peptides) enabling optimal stability and delivery capabilities. For example, the chemical composition of active U1 Adaptors can range from 100% 2’-O-Methyl (2’OMe) RNA nucleotides to 100% Locked Nucleic Acid (LNA) nucleotides, as well as mixmer configurations where a single U1 Adaptor contains varying amounts of each nucleotide. LNAs are a widely used nucleotide modification that confers increased annealing affinity and stability but too many LNAs (>50%) in an oligonucleotide can be problematic due to increased formation of self structure (hairpins) and oligomerization. Furthermore, phosphorothioate (PS) DNA bases can also be liberally “sprinkled” (U1 Adaptors with 100% PS bonds are fully active) into the U1 Adaptor design and bulky chemical groups such as biotin, peptides or fluorescent groups (e.g. Cy3) can be added at the 5’ or 3’ ends with no effect on activity. This makes U1 Adaptors superior to siRNAs or traditional ASOs that become inactive when so heavily modified. Such a chemically flexible platform allows the U1 Adaptor to be more highly stable and deliverable in vivo compared to siRNA or ASO.