Next-Generation Sequencing (NGS) in Drug Discovery & Development and Personalized Precision Medicine | Corning

Next-generation sequencing (NGS), also called massively parallel sequencing, is a technology that rapidly determines the sequences of millions of DNA or RNA fragments simultaneously. Because of its high speed and low cost compared to other methods, NGS is enabling researchers to gain a greater appreciation of human variation and its links to health, disease, and drug responses.

Recent advancements in NGS have opened up many possibilities in drug discovery and personalized medicine. The roles of these new technologies in drug discovery and medicine span from speeding up the identification of new drug targets to potentially helping clinicians choose the best drug for an individual patient.

Next-Generation Sequencing in Drug Discovery

According to Mars (Xuebin) Wang, Applications Manager at Corning, and Rae (Chia-Jui) Tsai, Ph.D., Genomics & Storage Product Line Manager at Corning, the ability to generate vast amounts of sequence data using NGS has revolutionized the process of identifying potential drug targets. By leveraging electronic health records, researchers can look for associations between genetic variants and specific phenotypes of interest within populations. In population-wide studies, NGS can aid in the discovery of mutations that are likely to cause disease.

Another important role is in target validation. Starting with a candidate drug target, scientists can use NGS to look for people with loss-of-function (LoF) mutations in the gene encoding that drug target. Combining phenotype studies with LoF mutation detection can help scientists confirm the relevance of a target and predict the potential effects of inhibiting that target with a drug.

Once a target is validated, NGS can inform drug design by providing insights into genome structure, genetic variations, gene expression profiles, and epigenetic modifications, Wang and Tsai explained. Once a candidate drug is ready for testing in patients, NGS can aid in the selection of patients for clinical trials of targeted therapies and can enable more precise patient stratification based on genetics within clinical trials. This can lead to smaller, more targeted trials with higher success rates.

NGS combined with innovative disease models, like patient-derived organoids, is also useful for drug repurposing and studying rare diseases. NGS allows for the efficient sequencing of DNA or RNA from organoids, providing valuable genetic and molecular information.

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NGS in Personalized Medicine

Next-generation sequencing also plays an important role in the development of personalized medicine, where it enables the customization of treatments based on individual genetic profiles and helps clarify how drugs may affect different patients depending on their genetics.

For complex diseases, NGS can help doctors precisely diagnose and classify patient conditions. Multiple NGS-based companion diagnostic tests have gained FDA approval, including liquid biopsy (blood draw-based) tests that help clinicians gauge patient eligibility for certain cancer treatments based on mutations found in their tumors.

In oncology, NGS can also help with the detection of minimum residual disease after treatment and with tracking the evolution of a tumor in an individual patient. For example, researchers are using patient-derived organoids and NGS to explore genetic heterogeneity among cells within single tumors and to understand how this heterogeneity contributes to drug resistance and poorer outcomes. In the future, clinicians may be able to use these techniques to evaluate tumor drug sensitivity and design personalized treatment plans for patients.

NGS can also be used to monitor the quality and stability of organoids over time by assessing changes in gene expression or genetic alterations. This helps ensure the reliability and reproducibility of organoid models for studying diseases and testing drug efficacy.

Variations in genes can also affect the absorption, distribution, metabolism, and excretion of a drug in individual patients, as well as a drug's efficacy or optimal dosing. NGS can aid in identifying these differences, an area of study known as pharmacogenomics.

Advantages of NGS in Drug Development

"By providing rapid and comprehensive genetic data, NGS significantly accelerates various stages of the drug discovery process, from target identification to clinical trials, ultimately reducing the time and cost associated with bringing new drugs to market," Wang explained.

NGS can streamline the drug discovery process in multiple ways due to these techniques' ability to efficiently and cost-effectively provide comprehensive genetic data from many samples, including both coding and non-coding regions of the genome. One example is that access to the data NGS provides can help scientists predict potential off-target effects and toxicities of candidate drugs early in the development process. Clinical trial designs that incorporate NGS results can potentially be more efficient and informative, streamlining the path to market.

Technological Advancements in NGS

NGS technologies continue to advance rapidly. Long-read sequencing is a newer set of technologies that can improve the resolution of complex structural variants and repetitive regions of the DNA. Single-cell sequencing allows gene expression profiles to be analyzed at the level of individual cells and is providing new insights into cellular heterogeneity, which is particularly useful in the cancer biology and developmental biology fields.

Other innovative techniques — such as spatial transcriptomics, liquid biopsy sequencing, epigenome sequencing, high-throughput functional genomics, and real-time sequencing — are advancing fields, from oncology to infectious disease research.

Great strides are also being made in the analysis of NGS data. "Next-generation sequencing generates vast amounts of complex data, necessitating advanced bioinformatics tools and software for efficient analysis and interpretation," Tsai explained.

Key advances include the use of cloud-based platforms that allow scalable and collaborative NGS data analysis, integrated analysis platforms that bring together multiple algorithms and tools to streamline the analysis process, and new visualization tools that allow researchers to interactively explore NGS data sets and interpret complex genomic features. Meanwhile, tools designed for specific applications, such as single-cell RNA-seq, are helping scientists perform specialized analyses.

Machine learning and artificial intelligence tools are facilitating multiple aspects of NGS data interpretation, such as variant calling, functional annotation, and predictive modeling. "AI-driven insights are increasingly used to predict the effects of genetic variants on protein function and disease phenotypes," Wang said.

Corning's Partnership for Drug Discovery

Corning Life Sciences is focused on providing high-quality comprehensive solutions tailored for drug discovery. In collaboration with researchers and industry leaders, we are developing new products to meet the increasing demand for accurate and cost-efficient NGS applications.

Corning offers high-quality labware and laboratory consumables that make automation easier and facilitate high-throughput NGS workflows. Products like the PCR microplate and customized consumables can help optimize sequencing workflows and minimize contamination. Our reagents and clean-up kits for sequencing can also help achieve streamlined and consistent sample preparation.

Corning's products for organoid culture, such as specialized cell culture surfaces and media, help researchers create and maintain organoids in the laboratory. These products provide the optimal conditions for the growth and development of organoids, enabling researchers to study their structure and function.

The combination of Corning's organoid culture products and NGS technology can be highly beneficial in various research applications. For example, researchers can use Corning's products to grow organoids and then use NGS to analyze their genetic makeup. This can provide valuable insights into the molecular characteristics of organoids, helping researchers understand disease mechanisms, identify potential therapeutic targets, and develop personalized treatment strategies.

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