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How CRISPR/Cas9 is improving drug development using zebrafish

Written by ALB on in the category Insights with the tags , , .


CRISPR/Cas9 came to the attention of scientists everywhere over five years ago. Ever since it hit the main stage, the gene editing technique has stayed in the spotlight, and for good reason. CRISPR/Cas9 has undeniably stretched the boundaries of what is possible when it comes to genetic manipulation; but to what end? BioVox wanted to know some of the more specific impacts this innovation has had, so we spoke to CRISPR/Cas9 expert Dr. Eric Paul Bennett from the Copenhagen Center for Glycomics at the University of Copenhagen and ZeClinics researcher Dr. Vincenzo Di Donato about the CRISPR/Cas9 impact on the challenging field of drug development.

At its core, CRISPR/Cas9 is a naturally occurring survival technique; it lets bacteria combat viral infections, by slicing the genetic material of an attacking virus. We’ve known about the existence of CRISPR/Cas9 since the 1980s, but it wasn’t until the Doudna and Charpentier labs studied it in 2012 that we grasped its full potential: CRISPR/Cas9 can be used to guide targeted gene alterations. In short, we can manipulate DNA like never before!

This increase in the flexibility and speed of generating animal models is a fantastic asset to the whole field of pharmaceutical science. - Vincenzo Di Donato, ZeClinics
 

CRISPR/Cas9 has been transformative across all genetically based scientific fields, from oncology to agriculture. So how has the technique affected the pharmaceutical industry? Dr. Di Donato, a CRISPR/Cas9 researcher at ZeClinics labs, explains:

“The advent of CRISPR/Cas9 has revolutionized the field of functional genomics. Compared to other technologies, the CRISPR/Cas9 system both shortens the time required to analyze gene loss of function and enables high-throughput genome editing. Thanks to this huge amount of data, we are now able to determine drug-target interactions in an extremely precise manner. It is a major step forward towards personalized medicine.”

Fast, effective and targeted drug development? Sounds like something the pharmaceutical industry would definitely be interested in!

Pharmaceutical crisis

The discovery and development of novel drugs and therapies is generally the domain of large pharmaceutical companies. In a sense, it has to be: developing a new drug takes enormous amounts of resources, often costing billions of dollars and taking decades to complete. Even with all these high-cost investments, very few drug candidates make it through the clinical trial process to be approved by regulatory bodies such as the FDA. Less than 10% of drugs entering Phase I clinical trials ever make it onto pharmacy shelves, leading to a productivity crisis for pharmaceutical companies across the globe.
This astronomically high attrition rate is caused by a variety of factors, but at the base of the issue are the leads generated by pre-clinical trials. This phase of research, in non-human test subjects, often produces drug candidates that fail at later stages due to issues with safety and efficacy. It’s in this key, pre-clinical phase that CRISPR/Cas9 is proving to be a real game-changer.

There’s a great future for the zebrafish as a pre-clinical disease model in the bio-pharmaceutical industry. - Eric Paul Bennett, UCPH
 

CRISPR/Cas9 to the rescue!

By using CRISPR/Cas9 to generate pre-clinical animal models, researchers are able to understand drug-target interactions better than ever before. Instead of relying on random mutations, CRISPR/Cas9 lets scientists design the genome of their test subjects with pin-point accuracy, leading to the generation of better drug candidates that can then be pursued in further clinical trials. Prof. Bennett confirms:

“The way by which you can inactivate or target any gene in the model animal’s genome has only been made possible through the use of CRISPR/Cas9. Previously, you had to invest a considerable amount of time, about a year, to generate a single mouse knockout model; now, using CRISPR/Cas9, you can generate that mouse in about a quarter of the time. This increase in the flexibility and speed of generating animal models is a fantastic asset to the whole field of pharmaceutical science.”

Dr. Di Donato elaborates: “Using the CRISPR/Cas9 system in model organisms increases the robustness and speed of drug target identification and validation processes. By gathering detailed functional data from different animal models such as rodents and zebrafish (our model at ZeClinics), we can improve early predictability of drug leads, which decreases the risk of late phase attrition due to efficacy or toxicity issues.”

Crispy fish

CRISPR/Cas9 methods are being used to generate all types of different models, but the technique really has a chance to shine when used in combination with Zebrafish. Currently underutilized in pre-clinical studies, zebrafish present a perfect opportunity to assess the safety and efficacy of potential new drugs by providing researchers with a cheap, rapidly-reproducing animal with a genome surprisingly similar to that of a human. They are also ideal for optimizing pre-clinical drug studies as zebrafish larva are practically see-through, meaning their physiology and the effects of a drug can be visually measured in a live body.

Using the CRISPR/Cas9 system in model organisms increases the robustness and speed of drug target identification and validation processes. - Vincenzo Di Donato, ZeClinics
 

Using CRISPR/Cas9 to produce genetically engineered zebrafish models lets you combine target validation with phenotypic assays, sequentially studied in the same individual animal. This plethora of preclinical data improves early predictability of drug targets and ultimately decreases the risk of late phase attrition. Dr. Di Donato concludes:

“The more information we can generate at preclinical stages, the more robust our conclusions will be moving downstream the drug development process. Now, the current focus is on target-based screenings, but phenotypic observations are also very relevant. This is where the combination of CRISPR/Cas9 with zebrafish comes really handy: not only can we analyze essential domains of any target protein, but we can also perform complex morphological and functional phenotypic assessments in the context of a non-invasive, in vivo assay. And all with within the same living individual.”

Prof. Bennett agrees: “What ZeClinics is presenting to the field of drug discovery is a cheap model organism where desired mutants can be quickly engineered using CRISPR/Cas9. The cost efficacy of zebrafish, coupled with designer genetics, is a great asset to the company and to the pharmaceutical field in general. There’s a great future for the zebrafish as a pre-clinical disease model in the bio-pharmaceutical industry.”

Image credit: Uri Manor, NICHD

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