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Early investment in drug discovery pays dividends

Early investment in drug discovery pays dividends

How our automated CRISPR workflows can accelerate your drug development programme towards clinical success

Drug development is a long and expensive process. Most estimates suggest that it takes between 10-15 years to complete the journey from drug discovery to regulatory approval, even longer for first in class treatments. During this time the pool of candidate molecules will narrow from an initial 5,000-10,000 possibilities to one single approved therapeutic. There aren’t any shortcuts here, but there is a notable swell of opinion to suggest that a rational, systematic and biology-led approach to target identification and validation, coupled with detailed mechanism of action studies in disease relevant cell models can improve the chances of eventual clinical success (Lu et al. 2017, Plenge 2016, Scannell et al. 2012, Croston 2017).

CRISPR / Cas technology provides a precise and efficient mechanism for rewriting a cell’s genetic blueprint, and the ability to delete, enhance or otherwise modify gene activity at will can prove invaluable as part of the drug discovery and development process. But robust and reliable gene editing at the scale required for a major drug development programme can swiftly become so laborious and time consuming that it no longer appears to be a viable solution. That’s where OXGENE comes in. From gold standard CRISPR library production and screening to automated, quality assured and flexible high throughput gene editing and disease modelling, we can help you achieve clinical success sooner.

CRISPR libraries and screening

Target identification

CRISPR screens – performed against either the whole genome, or specific gene families – allow unbiased discovery of genes that are either essential for cell survival or that confer a particular phenotype, such as drug resistance or sensitivity. This makes them an ideal tool for the discovery of new drug targets; CRISPR screens offer infinitely more efficient and reliable target identification than can be found by trawling through literature or genomics datasets.

Library design

OXGENE has extensive experience creating high quality lentiviral and plasmid gRNA libraries in pooled and arrayed format. We offer full genome KO and CRISPRa libraries, as well as rapid generation of libraries against specific gene families, such as the druggable genome, the kinome, apoptosis, cell cycle or the ubiquitin-proteasome system. Alternatively, we can rapidly generate a custom library tailored to your requirements.

Pooled screens

In addition to creating custom reagents, OXGENE can perform a whole genome pooled CRISPR screen and bioinformatics analysis in-house to provide you with a list of hits relevant to your research question.

Dylan Jones, one of OXGENE’s senior scientists, says: “A pooled CRISPR screen can take you from a starting point of thousands of candidate genes down to a handful. One of the real strengths of our pooled CRISPR screening service is the bioinformatics support we provide. Our in-house team can analyse a huge amount of screening data into a concise list of relevant potential gene targets. We recently carried out a screen to identify novel essential kinases in PC9 cells to determine potential new therapeutic strategies in the treatment of Non-small-cell lung carcinoma (NSCLC). At the end of the screen, bioinformatics analysis identified a very manageable list of potential targets for further validation.”

Arrayed screens

Arrayed CRISPR screens can be used as an alternative to pooled screens when the list of genes is small enough (e.g. hundreds of genes), or as an efficient means to validate a relatively large number of hits from a pooled screen. In an arrayed screen, Cas9 is introduced into all the cells, but unlike a pooled screen, a lentivirus containing a single gRNA is introduced into each individual cell population in parallel. This enables precise and direct quantification of the desired phenotype. When used as a form of hit validation, arrayed screens can refine your longlist of hundreds of candidate genes into a shortlist for further experimentation and analysis.

OXGENE leverages its expertise in automated gRNA design, high-throughput cloning and lentivirus production to provide custom arrayed libraries. We can also perform the entire arrayed screen in-house to provide you with a list of relevant genes for your desired phenotype.

High throughput gene editing

Target validation

It takes significant further experimental validation to progress from a shortlist of potential gene candidates to drug development, and this is another scenario where CRISPR/Cas technology is valuable. Depending on the studies you wish to perform at each stage, the generation of gene edited clonal cell lines is either a next step, or an alternative approach, to target gene validation.

Our automated gene editing platform is streamlined, optimised and quality assured. It can be scaled up to meet large scale or high throughput project demands – we can generate hundreds of custom edited cell lines per year – or scaled down to cater to smaller, more specialised projects. It’s an inherently flexible workflow that can accommodate any number of different starting cell types and biological characteristics, including both adherent and suspension cell lines. It’s also been adapted to allow high throughput editing of inducible Pluripotent Stem Cells (iPSCs).

If you’re further along the drug development process, and already have one or more molecule of interest, our high throughput platform can help you to identify, validate and study candidate genes whose loss might affect sensitivity to your new therapies, for example conferring resistance or further increasing sensitivity.

The quality of our edits and the reliability and functionality of our platform has been validated in previous projects, including during our partnership with Abcam, where we successfully generated hundreds of KO cell lines for antibody validation.

Pela Derizioti, who leads OXGENE’s Automated Gene Editing team, shares the secret to the platform’s success: “It’s teamwork, and the fact that every single person is willing to chip in and go above and beyond. The whole company has pulled together to make this platform work so well: the biologists, the automation team, the bioinformatics team, and the commercial teams.”

Studying the mechanism of action

One reason that novel compounds sometimes fail in clinical trials is through insufficient understanding of the biology underlying the drug’s mechanism. Many genetic diseases are the result of more than one gene knockout or other types of mutations entirely, and culturing primary cells from patients with these mutations can be very difficult. Our automated gene editing platform isn’t limited to creating CRISPR KOs. We can also generate clonal cell lines modelling complex disease scenarios, such as double knock-outs, knock-ins, gene fusions, chromosomal deletions or chromosomal rearrangements to help you make a full study of the mechanism of action of your putative compound and increase the chances of eventual clinical success.

We also recently optimised our automated gene editing platform to accommodate high throughput edits of inducible Pluripotent Stem Cells (iPSCs). These are a particularly powerful tool for disease modelling and drug discovery, because they retain the ability to differentiate into other cell types. However, they can be difficult cells to work with, because they’re prone to differentiate in response to cellular stress, and exhibit notoriously low editing efficiency. However, in another example of the flexibility of our automated gene editing platform, OXGENE is optimising our gene editing workflow to achieve a careful balance between cellular stability and editing efficiency.

Suzanne Snellenberg, Group Leader of OXGENE’s Complex Edits and Screening team says: “Automating our gene editing platform and combining this with in house expertise and bioinformatics software takes a lot of the risk out of creating a cell line containing a difficult or rare edit. For example, when the editing efficiency is low, we can implement strategies to enrich for these rare editing events. In addition, we can increase the number of clones to expand and screen by bioinformatics analysis to identify a successfully edited clonal cell line. We’ve now translated the experience we’ve obtained generating other complicated gene edits into providing customers with quality assured gene edited iPSCs”

Conclusion

OXGENE has both access to the latest CRISPR editing technology and considerable in-house expertise and experience to genetically engineer mammalian cells at unparalleled quality and scale, whatever stage of the drug discovery or development process you’re working at.

Our gene editing platform is supported by a culture of continuous innovation. We believe that delivering market-leading genome engineering technology is no excuse to stop seeking improvement. Whether driven by our in-house research and development pipeline, or a bespoke customer project, we are constantly improving the efficiency and accuracy of our platform.

We put a strong emphasis on communication with our partners, because we know that choosing a partner for a challenging scientific project is about more than just the final product. That’s why our relationship with our partners is paramount. From the first interaction with our business development team, our customers have a clear point of contact within OXGENE. Once the project begins, we set up a dedicated project team, spearheaded by a project manager and scientific lead. The customer will remain in direct contact with both the project manager and scientific team throughout the project, as well as having access to our in-house scientific data management portal to enable real-time access to project results.

Our ambition is always to build strong and lasting relationships with our customers to help transform the life sciences industry and accelerate the discovery and development of new therapies for the patients who need them.






© OXGENE 2020. All rights reserved. OXGENE is a trading name of Oxford Genetics LTD. Registered in England & Wales. Company No. 07617346.
Registered office: Medawar Centre, Robert Robinson Avenue, Oxford, OX4 4HG, United Kingdom

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