Purpose(s)
China’s "Fourteenth Five-Year Plan Outline" regards "persisting in innovation-driven, optimizing top-level design, and strengthening national strategic scientific and technological capabilities" as the main development goals and major tasks.
Introduction
The National Medical Products Administration (NMPA) currently does not have specific guidelines and technical guidelines for nucleic acid drugs. In order to standardize its pharmaceutical research and unify its evaluation standards, NMPA released a draft for comments on related gene therapy products in September 2020, soliciting opinions from the public. How to scientifically conduct and improve the preclinical toxicology research and careful analysis and evaluation of nucleic acid drugs to avoid the failure of clinical trials at an early stage has become an important challenge for the current international community.
Theme
The main content of preclinical toxicology research is the safety evaluation of drugs. Whether a drug is safe is a key factor in whether a drug can pass clinical trials. In the entire process of drug development, toxicity is one of the important reasons for the termination of drug development. Although there have been more in-depth studies on nucleic acid drugs, there are still many clinical adverse events that occur. Because nucleic acid drugs are different from chemical drugs and Chinese patent medicines, conventional in vivo and in vitro toxicological evaluations are difficult to deal with the potential risks of nucleic acid drugs. Nucleic acid drugs have many potential toxicity risks, such as the safety risk of the drug delivery system, the potential toxicity risks of "off-target" in the body of nucleic acid drugs, different targets for nucleic acid drug inhibition/degradation may have the risk of side effects such as carcinogenesis, and rapid degradation/accumulation in the body makes the dosage design of nucleic acid drugs difficult. All of these have brought challenges to preclinical toxicology research.
At present, most nucleic acid drug toxicity evaluation studies at home and abroad focus on the analysis and evaluation of genotoxicity through Ames experiment, comet experiment, etc., multi-omics joint system analysis of changes in Biomaker to reflect drug response, computational toxicology to predict genotoxicity, model organisms (Nematodes, Zebrafish, etc.) and biomimetic systems (3D cells, organoids, etc.) toxicological evaluation, etc. Our research group has also made a lot of attempts in the preclinical toxicology research of nucleic acid drugs, establishing a related toxicity prediction website (LTMap) and conducting toxicity evaluation through miRNA and mRNA gene chips.
Summary
The value and challenge of nucleic acid drugs coexist. With the continuous advancement of science, we believe that there will be standardized, uniform, and feasible standards for preclinical toxicology studies of nucleic acid drugs, making the launch of many nucleic acid drugs just around the corner, bringing revolutionary contributions to life sciences and medicine.