Predicting oligonucleotide therapeutic efficacy at the population level

DNA-directed RNA interfering (RNAi) mediators that follow the classic Watson-Crick base pairing to bind to their molecular targets and exert their silencing capacities have been identified to be relatively insensitive to single nucleotide polymorphisms (SNPs). The experimental evaluation of a few putative genomic SNPs in a quasi-species population is the only approach scientists have been employing so far for the experimental validation of the efficacy of oligonucleotide drugs on a given population. These studies are inherently constrained by the number of SNPs that can be experimentally supported in the context of an identified molecular target.

To address this sampling limitation, we have developed a method to report the relative sensitivity of all known and unknown polymorphisms to a prospective therapeutic drug. The power of ultra-deep next generation sequencing (NGS) allows us to test drug effect in vitro on all possible SNPs of a molecular target, in a patient-free manner. We are presenting the technical details to our approach that is empowering unbiased pharmacodynamic studies at the population level for sequence-specific oligonucleotide drugs and genome editing tools.