CRISPR: Five Ways to Maximize Its Potential - Drug Discovery and Development

In 2011, only 86 articles in the scientific literature cited the gene-editing technology, CRISPR (clustered regularly interspaced short palindromic repeats). By the end of 2016, that number had increased more than 20-fold to 2186, with the majority of the research originating in the United States and APAC.

Today, CRISPR is dominating the headlines, and it will continue to do so, both in scientific publications and in the lay press. The latter will drive curiosity and fantasy — for example, a recently released “thriller” novel focuses on CRISPR, and Jennifer Lopez is said to be working on a TV series based on the technology.

But more importantly, for scientists who can keep pace with the rapidly shifting landscape the burgeoning number of studies will spur and inform new research, bringing CRISPR that much closer to the clinic.

As the groundswell behind CRISPR grows, pharmas and biotechs will need to have systems in place that enable their R&D teams to make the most of new insights and rapid developments in the field. Here are five ways to help ensure that happens.

1. Mine all available data. To take advantage of CRISPR and help move the field forward, companies need to have access to all relevant information, including experimental, sequence, mutation and clinical data, as well as published clinical studies.

But that’s just the beginning. The data is useless until it is aggregated, structured, normalized and integrated so it can be used to inform decision making about what to snip and replace. This requires robust analytical systems that can process multiple types of data sets (e.g., gene expression, protein-protein interactions, cellular processes, disease mechanisms, etc.) and use entity recognition and pattern matching software to identify meaningful relationships among those entities.

Increasingly, systems will also be required to analyze input from nontraditional sources such as social media. To that end, companies will need to leverage emerging technologies such as sentiment analysis – using computational linguistics and biometrics to mine opinions – to separate potentially meaningful input from noise. And they will need to do all this quickly, accurately and continuously.

2. Collaborate. The days of bench scientists operating in silos, or companies doing everything on their own, are over. The best science today is being done by interdisciplinary teams made up, among others, of scientists and clinicians with expertise in genetics, disease mechanisms, computer modeling and data analytics, and by companies that understand the power of precompetitive collaboration.

In fact, in her keynote address at SXSW 2017, CRISPR pioneer Jennifer Doudna of UC Berkeley noted that the technology itself was developed via a collaborative effort among professors, academic institutions, students and others.

Last year, an article in Nature pointed to the CRISPR patent dispute between UC Berkeley and the Broad Institute as an example of how the “pursuit of profit poisons collaboration.” Yet, collaborations are moving forward nonetheless. On May 16, for example, Target ALS Foundation, a privately funded consortium of academic and biotech/pharma researchers that aims to accelerate new treatments for amyotrophic lateral sclerosis, awarded a grant to biotech CRISPR Therapeutics to support preclinical discovery. In turn, CRISPR Therapeutics will collaborate with researchers at the University of Florida to test the technology in disease models.

Elsevier’s innovation hub, called The Hive, is fostering collaborations and accelerating research among biotechs and pharmaceutical startups by providing access to various R&D information technologies. Hive member Rubius is using a technology akin to CRISPR involving the use of genetically engineered red blood cells to deliver therapeutics. Rubius’s team also is made up of collaborators — i.e., individuals from the pharmaceutical industry and investment/entrepreneurship.

Patient advocacy groups also are stepping up as valued collaborators. For example, the U.K. nonprofit Findacure is driving efforts to repurpose off-patent drugs as treatments for rare diseases. Patient groups not only help publicize the organization’s efforts, they provide fertile ground for recruitment of trials of candidate drugs, which may in the future include CRISPR-based therapies.

3. Keep up with regulatory requirements. Like any potential new treatments, CRISPR gene editing-based therapies will need to go through preclinical studies, clinical trials and postapproval distribution and monitoring. How regulatory agencies address issues that arise at each of these steps will likely take years to evolve, and it behooves companies to keep current to avoid having to scramble later on, or be forced to duplicate earlier efforts.

In January, the FDA issued three proposed guidance documents that would expand existing guidelines to cover CRISPR and other genome-editing technologies in animals; address genome-editing for crops; and delegate the regulation of mosquitoes created for pest control to the Environmental Protection Agency’s pesticides program. Nothing has emerged yet regarding CRISPR use in humans, but such guidelines surely are coming.

Critical questions need to be answered before such regulations are put firmly in place, however. How to assess safety and efficacy? How long will effects last? Will germline CRISPR edits affect future generations? Is there an off-switch if a gene edit turns out to be harmful? If not, does an off switch need to be created before a gene-editing treatment is approved? What are the side effects — anticipated and unanticipated? The study of off-target CRISPR mutagenesis is underway, but is as of now incomplete. Can animal studies be relied upon to inform safety in humans? Can gene editing lead to the evolution of more robust pathogens or pests?

It is highly likely that regulatory process development will be incremental; as data emerge and are validated in specific areas, regulations will start to appear. It’s analogous to when monoclonal antibodies came on the scene. First there were small-molecule drugs, and regulations were put in place to assess and monitor them. Then monoclonal antibodies (mabs) began to appear, and many of the issues were similar to what we’re facing with CRISPR: what will happen with large-scale use? How can we anticipate unwanted side effects and adverse reactions, and monitor patients for safety? With CRISPR, we will have a whole new class of treatments to deal with, just as we did with mabs.

While awaiting regulations, companies developing CRISPR applications would be wise to invest in systems that allow them to continuously monitor and document their efforts to understand the ramifications of promising treatments, and aggregate findings from all relevant publications, meeting presentations, experimental and clinical work, so they can more easily jump-start a CRISPR-style pharmacovigilance strategy when required.

4. Think ahead. I was recently asked to think 50 years ahead — to imagine the CRISPR landscape in 2067. Consumer entertainment takes us there easily; books, TV and movies can let the imagination run wild without any real-world constraints. But science moves much more slowly, and given the current limits of our understanding, and the regulatory requirements on the horizon, 50 years really is not a long time at all.

Nevertheless, it is my hope that within the next 50 years, we will be well beyond the recent achievement by Stanford University researchers, who succeeded in using CRISPR in stem cells to repair the gene that causes sickle cell disease and in transplanting the mended cells into mice. Hopefully, we will be treating humans by then, and making inroads against the hundreds of other rare and orphan diseases that plague humankind — and possibly more common conditions such as hypercholesterolemia.

I also envision advances in CRISPR work in other domains, particularly plants. Can CRISPR technologies significantly reduce world hunger?

5. Be patient. In her SXSW keynote, Doudna acknowledged her fear that people will get so excited about CRISPR that they start to deploy it before it’s ready, possibly inducing a backlash if harmful effects emerge, as happened in the 1999 U Penn gene therapy trial. A backlash is a real possibility, given the concerns that have already emerged regarding the partial success of a team in China in correcting genetic mutations in normal embryos. This has spurred similar studies and will undoubtedly continue to do so, but much remains unknown.

Just as the widespread application of antibiotics has led to the development of resistant organisms, we don’t know what widespread application of CRISPR techniques can lead to in insects and plants, much less humans. Caution is advised. Let’s tread slowly and safely, learning as much as possible along the way, and sharing our experiences to help ensure our dreams for this powerful new technology are realized.

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About Dr. Matthew Clark:

In his role, Clark leads the global pharmaceutical consulting practice for Elsevier; where he works with pharmaceutical companies to deploy data integration, text mining, and custom bio-informatics solutions. Previous to this role, Mark worked at AstraZeneca as an analyst in safety pharmacology. Before this Mark was the Director of Scientific computation (R&D IT) at Locus pharmaceuticals. Throughout his career Mark has published over 25 publications in pharmacology, predictive modeling, and chemistry.

Clark recently gave the talk, “CRISPR’s Impact on Society and Science” at the R&D 100 Conference held Nov. 16-17 in Orlando, FL. For more information visit https://www.rd100conference.com/

About Elsevier R&D Solutions:

Elsevier R&D Solutions delivers the latest research and published scientific literature relating to CRISPR, to a number of life sciences organisations. ‘The Hive’, an incubator for biotech start-ups developed by Elsevier to give four start-up companies free access to their suite of solutions, is supporting the research of Rubius Therapies – which is conducting its own gene editing research, facilitated by the use of Elsevier’s tools.