Oligonucleotide-based therapeutics have potential application across a broad range of indications, including those not addressed by traditional large/small molecule approaches
Oligonucleotide–based therapeutics modulate gene expression by selectively targeting mRNA via hybridization of the nucleic acid sequence of the therapeutic to the cognate natural genetic sequence. Oligonucleotide-based therapies are highly specific for target genes and are able to down-regulate or otherwise modify genes that are responsible for disease. A key distinguishing attribute of nucleic acid drugs is their ability to access the “undruggable” space left by small molecules and biologics, allowing drug developers to address a wider range of diseases, and particularly those with limited or no therapeutic options. In addition, given the mechanism of action, oligonucleotide-based therapies typically have a long duration of effect which translates into less frequent dosing relative to other therapeutic modalities.
At Aro, we have developed capabilities to design and optimize oligonucleotides
The most common forms of oligonucleotide-based therapeutics are small interfering RNA (siRNA) and antisense oligonucleotides (ASO). Recent advances in nucleic acid chemistry have improved stability, bioavailability, specificity and potency of oligonucleotide-based therapeutics. However, the full potential of oligonucleotide-based therapies has not been achieved, for it has proven challenging to achieve sufficient targeted uptake of these therapies in tissues outside of the liver.
We have achieved compelling gene knockdown in extrahepatic tissue with both Centyrin-siRNA and Centyrin-ASO conjugates
siRNAs are double stranded RNA molecules that function by base pairing to target mRNAs, binding to cytoplasmic RISC (RNA Induced Silencing Complex) and cleaving target mRNA to modulate protein expression.
Antisense oligonucleotides (ASOs) are single stranded oligonucleotides that function by base pairing with pre-mRNAs or mRNAs in the nucleus, and that can modulate RNA splicing (i.e., exon skipping or exon inclusion), block protein binding to mRNA, or induce gene silencing by RNaseH mediated cleavage.