Employing Genomics Tools to Accelerate Drug Development

The use of functional genomics tools can accelerate the progress of new biotherapeutic candidates through the clinical pipeline. Functional genomics applies genetic, molecular, and cellular methods to elucidate gene function, the basis for target validation, according to Mark Behlke, MD, PhD, chief scientific officer, Integrated DNA Technologies (IDT), a US-based company that specializes in the development, manufacture, and marketing of nucleic acid products.

Today, the use of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 (Cas9) systems allows for functional genomics studies on all or subsets of genes with reduced noise and reduced off-target effects compared to RNAi methods (1,2), Behlke states.

“CRISPR studies can be designed to result in permanent gene knockout at the DNA level (CRISPRn) or to give transient gene suppression (CRISPRi) or activation (CRISPRa) at the transcriptional level (3). Combining both RNAi and CRISPR screens might actually give a more complete understanding of gene function than use of either method alone (4),” says Behlke. He adds that large-scale CRISPR screens were originally performed using pooled lentiviral expression methods in cell culture.

More recently, however, improvements in reagent manufacturing and high throughput screening robotics have allowed CRISPR screens to be performed in an arrayed format, which provide results quicker and with cleaner definition (5). After a target is identified, validation proceeds more slowly by thoroughly examining the subset of “hits” in primary cells, stem cells, organoids, small-animal disease model systems, and other approaches (6), Behlke explains.

“The latest advances in CRISPR methods now enable high throughput screening in zebrafish (7), permitting early target identification and validation studies to be performed in an intact organism and not simply in cell culture (8). These advances are dramatically altering the quality of data in the early target discovery and validation stage and are improving the pace of drug development,” says Behlke.

He further explains that whole genome CRISPR studies can generate large amounts of data, particularly when performed as high content screens (HCS), in which genetic changes are linked to phenotype via imaging. In addition, machine learning methods are now being applied to advanced functional genomics screening to improve target discovery, hit stratification, toxicity testing, etc. (9).

References

1. B. Evers, et al., Nature Biotechnology 34 (6) 631–633 (2016.).
2. I. Smith, et al., PLoS Biol. 15 (11) e2003213 (2017).
3. C. Bock, et al., Nat Rev Methods Primers 2, 8 (2022).
4. D.W. Morgens, et al., Nat Biotechnol. 34 (6)634–636 (2016).
5. J. Tan and S.E. Martin, PLoS ONE 11, e0168968 (2016).
6. B. Haley and F. Roudnicky, Cancer Cell. 38 (1) 31–43 (2020).
7. A. Vogt et al., J. Vis. Exp 40, 1-4 (2010).
8. C. Cornet, et al., Frontiers in Pharmacology, 9, 703 (2018).
9. A. Mullard, Nature Reviews Drug Discovery 18, 653–655 (2019).

About the author

Feliza Mirasol is the science editor for BioPharm International.

Article Details

BioPharm International
Vol. 35, No. 6
June 2022
Page: 14

Citation

When referring to this article, please cite it as F. Mirasol, “Employing Genomics Tools to Accelerate Drug Development,” BioPharm International 35 (6) 14 (2022).