Liwen Gao, study director at WuXi AppTec, looks at the importance of early and comprehensive genetic toxicology testing.
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Toxicology testing concept
In 1944, Avery, Macleod, and McCarty discovered that DNA carries genetic information. Nine years later, Watson and Crick decoded its structure. Since then, scientists have worked hard to understand how outside agents can damage the genome through the field of genetic toxicology, which assesses the effects of xenobiotics on DNA and the genetic processes of living cells.
Over the decades, several major landmarks have advanced our understanding of DNA damage. In the 1950s, it was accepted that chemicals other than radiation could also cause harm. In 1973, Bruce Ames invented the Ames test, a rapid bacterial mutagenicity assay, which became the most famous and widely used test in genetic toxicology.
In 1981, OECD began publishing the first test guidelines for genetic toxicology, and by the end of the decade, almost every major regulatory body required genotoxicity testing batteries for pharmaceuticals. In the early 2000s, advances in PCR, sequencing, and imaging reshaped the field entirely. New methods on the horizon promise to make genetic toxicology even more precise. Over time, the practice has become an increasingly crucial element of drug development, and it’s a regulatory, ethical, and practical imperative that sponsors understand the degrees of damage genotoxic agents can cause.
Today, genetic toxicology is a fundamental cornerstone of drug development. Early, well-designed genetic toxicology studies protect patients from harm and save time, money, and effort for developers, who must give them the appropriate level of care and concern to ensure they are not treated as just another box to tick in the development process.
Establishing patient safety through genetic toxicology
Among the many reasons genetic toxicology is so necessary, patient safety is the most crucial. Unlike other forms of toxicity, genetic toxicity is often permanent and irreversible. The damage can cross cell generations, and DNA mutations can trigger secondary malignancies or heritable defects years after treatment.
The dangers of genotoxicity include gene mutations and chromosomal aberrations, and can lead to cancer and teratogenic effects, which can cause birth defects. The severity of these impacts and the potential suffering they can cause patients make it imperative to address the issue early and comprehensively by examining whether new or existing chemicals intended for human use affect DNA.
How early data prevents late-stage failure
Drug developers who treat genetic toxicology as merely a checklist item can find themselves facing costly delays or failures. Neglecting this crucial part of the development process can delay the start of clinical trials or result in wasted resources if a drug is later found to pose a genotoxic risk.
To avoid these troubles, developers must embrace early-stage genotoxic testing. Early genotoxicity data can profoundly influence the entire lifecycle of a drug’s development and is sometimes a determining factor in whether a drug progresses to trials, shaping the scope, cost, and timeline of subsequent studies.
If a drug is found to be genotoxic and has no acceptable risk-benefit profile in early testing, it can be dropped before more expensive studies are carried out, following the mantra: “fail early, fail cheaply.”
Early studies, such as the Ames test, can also reveal structural concerns, including reactive electrophiles, aromatic nitro groups, and DNA-intercalating structures. Researchers can use these findings to modify structures, remove reactive metabolites, and improve stability, reducing the risks of genotoxicity while maintaining chemical flexibility.
Early data is crucial even in circumstances where more risk is tolerated. If a drug is targeting a life-threatening condition such as advanced cancer, genotoxicity should still be a priority. Developers must still recruit volunteers with life-threatening diseases, which can be a lengthy process. Therefore, they often run pharmacokinetic (PK) studies first on healthy volunteers. In these cases, early genotoxicity data are critical to support the execution of the PK studies.
Ensuring a smooth regulatory pathway
Genetic toxicology testing is also an integral part of the international safety framework. ICH S2(R1) states that every drug candidate must undergo defined in vitro and in vivo assays before progressing to first-in-human studies. This means regulators pay close attention to genotoxicity evaluations, which play an integral role in the basic toxicological information package used in decision-making and risk assessment. The guideline also serves as a playbook for the standard test battery, outlining when and how to conduct follow-ups and how to interpret results.
No single test can detect all relevant genotoxic endpoints, so regulators recommend a combination of in vitro and in vivo tests. Sometimes, developers may need to modify the standard test battery. For example, if a drug candidate is toxic to bacteria, one of the in vitro mammalian gene mutation assays should also be conducted.
If a compound yields positive results in the standard test battery, researchers must conduct further testing. If there is a positive result in an in vitro mammalian cell assay, for example, researchers should ensure there are clearly negative results in two well-conducted in vivo assays in appropriate tissues and with demonstrated adequate exposure.
The future of genetic toxicology
Developers must always keep one eye on the horizon for new techniques and technologies that could change how genotoxicity is assessed. New Approach Methodologies (NAMs) are currently undergoing evaluation to support pre-clinical safety assessments in the pharmaceutical industry, and methods such as microphysiological systems and in silico modelling are proving reliable. These techniques may be valuable to researchers and regulatory agencies as they can help streamline and standardise genetic safety testing, lower costs, and reduce reliance on in vivo testing.
One of toxicology’s most significant limitations is its reliance on non-human, oversimplified biological systems, which can yield data of questionable relevance, leading to false positives and missed hazards. A human-based model incorporating new technologies such as Deep Sequencing (DS) is highly anticipated in the industry.
A final word
The consequences of overlooking early genetic toxicology can be dire. Scientists and sponsors should pay careful attention to this part of development, ensuring it’s carefully considered and carried out early on. This can save time and money and improve development programs.
As technologies improve and new models enhance human relevance, the field of genetic toxicology may change, but the principles of early assessment, methodological rigour, and transparent interpretation will remain constant.
Ultimately, safeguarding the genome ensures patients are adequately protected, and that responsibility should be addressed comprehensively well before the first clinical dose is administered.