siRNA powerful tool We know the conventional chemotherapy has it’s limitation due to off targeted delivery of taxanes resulting in healthy cell death, intracellular resistance due to sub therapeutic concentration of taxanes and efflux (the drug get pumped out of the cells) effect among others so that is where the targeted delivery technology is supposed to mitigate those limitations by increasing the intracellular concentration of taxanes and escaping the efflux due to the fact they won’t trigger the proteins involved in initiating the pump so the taxanes can stabilize the microtubules and minimize the cell divisions and that is where THTX is at now, but they want to go further with their technology using siRNA as their new weapon against cancer. The reason is cancer is also associated with gene defects which explains why incorporating genetic materials is a powerful tool to treat various cancers where conventional anticancer medications have failed. The RNA interference inhibits the messenger RNA that signals uncontrollable cell growth by delivering “noncoding RNA” (siRNA among others) into cancer cells which trigger the degradations of mRNAs (selective gene silencing). So basically the purpose of small interfering RNA is to degrade the messenger RNA which is behind the cell proliferation. This is another powerful tool to create a therapy for the heterogonous cancer. The challenges with the gene therapy is tumor localization, off target effects, low stability and rapid clearance from the blood circulation (short duration and limiting treatment efficiency), cell and blood barrier, sounds familiar? To mitigate some of those issues THTX is now exploring the potentials of a peptide siRNA conjugate as they are actively searching for scientist with experience/knowledge of the gene therapy.
The targeted delivery using ligands resulting in accumulation of drug in cancer tissues can enhanced permeability and retention in tumor blood vessels bypassing the blood barriers and as for cell barrier due to the fact that naked siRNA is negatively charged( same as cell membrane) also water soluble the molecule alone cannot passively enter into cells so that’s where transmembrane transport by endocytosis is a useful technology which is also used in THTX' PDC technology so basically the ligand conjugated to the siRNA, binds to its receptor on the cell surface and is internalized via receptor mediated endocytosis releasing the siRNA into the cell and the receptor is recycled back to the cell surface.
The genetic manipulation although not new has many indications/possibilities and now due to successful mRNA Covid19 vaccines the technology is even more in the spot lights for treatment for various conditions least and not last many cancers, that is why THTX’s attempt to create a conjugate carrying the molecule to where it should go is surely justified and if successful sensational!