Research Projects

SOCIO-TECHNICAL CONTEXT AND PROBLEM STATEMENT: Under the $1.3 billion BioE3 policy of India aiming at revolutionizing domestic high-performance biomanufacturing, precision therapies such as oligonucleotide therapies (antisense oligonucleotides or ASOs and small-interfering RNAs or siRNAs) have a strong current and future market outlook. Combined, they are projected to reach a global $18 billion market valuation by 2031-2033 with 17-18% CAGR, attracting investments from all major biopharma manufacturers. However, the success of the drug relies on clinical trial data, which in turn is dependent on drug pharmacokinetic (PK) analysis among other parameters (Nucleic Acid Therapeutics, 2023, 33, p83, DOI: 10.1089/nat.2022.0054). The oligonucleotide drug PK in preclinical or clinical models is usually studied by liquid chromatography mass spectrometry (LC-MS), hybridization enzyme-linked immunosorbent assay (ELISA), and (for siRNA only) quantitative reverse transcriptase-PCR (qRT-PCR). While routinely used by industry, all three methods are centralized, costly instrument-reliant, and expensive. Conducting drug PK would thus imply biofluid transportation cost to central labs, disincentivizing the pharma companies to test experimental oligo drug at resource-constrained settings (Lancet Glob Health 2025, 13, e749). Therefore, method(s) enabling oligonucleotide drug PK measurement at remote settings would greatly benefit not just drug manufacturers, but also patients in need as well as domestic biomanufacturing. ************* OUR DISCOVERY, TEAM EXPERTISE, AND CONNECTION TO RESEARCH PROBLEM: We have recently discovered an unusual 3’-phosphorothioate (PST) mismatch processing capability by at least one strand displacement DNA polymerase, leading to isothermal rolling circle amplification (RCA). Incidentally, PST linkages are ubiquitous features in all gapmer-class ASO (6 approved as of 2023) and the majority of siRNAs (5 approved as of 2023) backbone. We also have recently reported a highly sensitive redox-mediator free electrochemical chalcogenide sensor for nucleic acid detection. Combining our discovery with our strong existing expertise involving electrochemical biosensing in carbon, oxide, and porous transition metal chalcogenide electrodes, we anticipate that a specifically tailored miniaturized electrochemical nano-biosensor to detect PST oligonucleotide drug candidates from biological samples is feasible. ************* THE PROPOSAL: We therefore propose harnessing the 3’-PST mismatch bypass amplification to fabricate a novel chalcogenide-based electrochemical biosensor platform for detecting a commercial antisense oligotherapeutic drug TEGSEDI (approved 2018) from cell culture model. Given that electrochemical sensors and electrodes are portable in nature, we anticipate that this innovation would act as a pivot to incentivize the pharma companies towards expanding the scope of experimental oligotherapeutic drug testing at remote settings, in turn benefiting the population in those areas.