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CRISPR and ZFN, Two Promising Gene-Editing Platforms

Though the underlying mechanism is said to have been initially discovered in 1987, the potential to use CRISPR/Cas9 (“CRISPR”) as a gene editing therapy has recently enthralled the media since its first application in 2013[1]; touting its “blockbuster” potential to “revolutionize” modern medicine as we know it. While the application of this underlying biological mechanism is not without its merits, CRISPR has not yet established itself as a therapeutic platform Given its nascence, the CRISPR platform could go on to prove itself as an efficacious therapeutic strategy but let’s also not get so caught up in its potential that we overlook the substantial progress and achievements of some of the of the other gene-editing platforms such as Zinc Finger Nuclease (“ZFN”).

Other than CRISPR, ZFNs and TALENs (transcription activator-like effector nuclease) comprise some of the most commonly used gene editing techniques. While TALENs are also relatively new, ZFNs have been around for over twenty years, with the ZFN gene-editing application taking place as early as 1994. Because of this history, ZFNs are too often described as being outdated, archaic, or obsolete.  While such sentiments might be true if we were talking about the next generation of smart-phones, this is an apples-to-oranges debate with respect to the biopharmaceutical industry where “new” and “promising” are synonymous with “high-risk” and “unproven.” And while older technologies can often lack the redeeming qualities and attributes of their successors, they also tend to have a track record of reliability.

Think about this: what will you do on your next road trip if your GPS ceases to function properly? You would have to learn how to use a map, which while outdated as a navigation tool, is proven and reliable.  Similarly, while some critics may view ZFNs being older as a bad-thing, I would argue that this is actually why ZFNs should not be discounted as a promising platform for gene-editing based therapies. Yet, not everyone agrees. This article will focus on two reasons why Zinc Finger Nuclease should continue to be viewed as a viable gene-editing solution based on its history: longevity and barriers-to-entry.

Longevity

The ZFN platform has a robust track record, established through a long history of use, which translates to over two decades of research and development that has refined, optimized and validated ZFNs for therapeutic application. The same can’t be said of TALENs and CRISPR.

ZFNs also have a good safety profile as they and have been tested in over one-hundred patients participating in clinical trials for various genetic diseases[2]. ZFN is the first gene-editing platform to edit genes: ex vivo, in vivo, and in humans and first entered the clinic in late 2017. CRISPR, however, is not far behind as it was just recently announced that CRISPR Therapeutics partnered with Vertex to launch the first CRISPR gene-editing trial in humans.[3] However, the FDA recently put the US Phase 1/2 on hold for unspecified reasons but the same trial remains open for patient enrollment in Germany. China tested CRISPR on the first-patient in 2016[4].

Barriers-to-Entry

In addition to a long period for research and validation, the ZFN platform also benefits from barriers-to-entry, namely a consolidated patent estate and technological know-how.

Sangamo Therapeutics is the dominant user of ZFNs for gene-editing. They have been actively developing the platform since 1995 for a multitude of genetic diseases and disorders. With a market cap of just over a billion dollars, Sangamo has engaged in several large partnerships for the development of drug candidates; inking deals with Pfizer, Shire, Bioverativ (Sanofi), and most recently, Kite Pharma (Gilead).[5]

Patents

In almost any tech-based industry, whether it is software, biotech, or mechanical, patents are the bedrock on which companies stake their ground. So it should come as no surprise that a robust patent portfolio is but one of several desirable features of a drug candidate/program. However, since CRISPR and ZFN are completely different gene-editing techniques, if we really want to compare CRISPR to ZFN from a patent perspective, we need to look at their patent landscapes. In other words, we need to look at the ownership/allocation of all respective patents within the CRISPR and ZFN fields.

Taking a look at the ZFN-space, it is clear that Sangamo has the dominant patent estate with regard to ZFN.[6] In fact, they are so dominant that there is no direct competition with regard to using a ZFN platform to treat Sangamo’s diseases of interest, which is why they are the only major player in this space and their various partnerships likely have a lot to do with this. Co-Development partners want to be assured that the likelihood of a direct competitor is minimal before they invest potentially billions of dollars into a drug program.

The CRISPR patent landscape is quite different. For starters, there is no dominant estate; in fact, it’s quite the opposite. There are multiple players actively pursuing CRISPR-based therapies: Editas, CRISPR Therapeutics, Intellia Therapeutics, and Caribou Therapeutics are the most notorious. All of these companies are currently battling each other in the courts and at the patent office (via their academic licensors) for rights to the seminal CRISPR patents.

There has been plenty of media coverage on this patent dispute but to briefly summarize: Editas was spun-out of the lab of Dr. Feng Zhang of the Broad Institute. Intellia, CRISPR Therapeutics, and Caribou Therapeutics were spun out of the lab of Dr. Jennifer Doudna of the University of California. The essential issue at hand – who invented the therapeutic application for CRISPR first?[7]

Editas currently has the upper-hand as the Court of Appeals for the Federal Circuit (CAFC) recently upheld the decision rendered by the patent office in awarding the patent rights to the Broad Institute.[8] The only thing that University of California and its various licensees can do now is appeal to the Supreme Court. Given that the Supreme Court only hears 1% of the cases it receives, this may well be the end of the dispute. On the other hand, the media attention and ground breaking potential of CRISPR may be enough to persuade the court to take on the case.  We will likely not hear about the Supreme Court’s decision until early 2019 and if it turns out that they do decide to take this on, the patent bar, along with the rest of the scientific community, will hold its breath as the Supreme Court has become somewhat notorious for creating greater confusion with some of its more recent holdings in cases where patents are involved. Until this is finally over, CRISPR stakeholders will face a great deal of uncertainty.

Know-how & Synthesis

The synthesis/engineering of the ZFNs themselves has historically been viewed as difficult and time consuming. While this used to be the case, it may not be accurate today. According to Sangamo’s VP of Technology, the time it takes them to identify and get to a final therapeutic ZFN candidate is three months, whereas it used to take them the full year. Sangamo has undoubtedly acquired an abundance of know-how with regard to the manufacture and optimization of ZFNs. To the extent this know-how never made it into a patent application, Sangamo has effectively erected another formidable barrier to entry for would-be competitors. As a result, Sangamo is well-positioned as prospective competitors would have to retro-engineer any proprietary manufacturing techniques that Sangamo may be intentionally safe-guarding from the patent literature.

But what about using ZFNs as tools for basic research; particularly in an academic setting? In this case, ZFNs don’t make a whole of sense for the same reasons above. How many grad students or researchers have the capability to manufacture ZFNs, or have the time, even if it only takes three months? In the research arena, CRISPR is more straight forward and efficient for gene-editing, which I would argue actually hinders its appeal as a potential therapeutic platform.

FDA-approved drugs and therapies need to be prescribed by a physician and it’s difficult to buy these drugs legally via the internet (the regular internet not the dark web). This is not the case for CRISPR and it may not be the case even if it is ultimately approved for human therapeutic applications. That is because there are literally hundreds, if not thousands, of Do-It-Yourself (DIY) CRISPR guides, kits, materials, etc.[9] Because of the accessibility and ease of creation, CRISPR poses many challenges from a patent enforcement standpoint and thus establishing a commercial market. In contrast, the average lay person and/or grad student can’t make ZFNs in their garage, or at least not at the same massive scale as the CRISPR-DIY market.

Final Thoughts

(1)The main intent of this post is to educate and make those reading aware that CRISPR is still in the very early stages of development despite its very positive outlook in the media. Over the last several months there has been a flurry of peer reviewed literature that sheds light on some of the serious problems scientists have had with the therapeutic application in animal and in in-vitro models and this has been reflected in CRISPR companies’ stock prices. But that’s not to say that ZFNs, or even TALENs, aren’t without their fair share of setbacks as off-target editing/binding seems to be a common plague amongst all three platforms. Even Sangamo, with its twenty-year head start, had a recent clinical setback when the data readout from one of its recent trials was less than ideal.[10] CRISPR as a gene editing platform is still in its infancy and will likely incur many more setbacks throughout its clinical development, just like the ZFN platform. Only time will tell which will prevail and/or if both methodologies can coexist in the therapeutic realm.

[1] https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crispr-timeline

[2] Emphasis on “safety.” Early/phase 1 trials are all about safety and tolerability. Thus, we can’t say with any high degree of certainty that ZFNs will actually be efficacious in treating any particular disease as more clinical/patient data is being gathered as we speak.

[3] https://www-bizjournals-com.cdn.ampproject.org/c/s/www.bizjournals.com/boston/news/2018/08/31/crispr-vertex-launch-first-company-backed-gene.amp.html

[4] https://www.nature.com/news/crispr-gene-editing-tested-in-a-person-for-the-first-time-1.20988

[5] https://www.reuters.com/article/us-sangamo-deals-gilead-sciences/sangamo-in-3-billion-gene-editing-deal-with-gilead-idUSKCN1G61HZ

[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2733216/?_ga=2.144751284.1417183324.1536248960-1738662770.1528291886

[7] http://www.ipwatchdog.com/2018/08/17/crispr-tug-of-war/id=100378/

[8] https://www-mercurynews-com.cdn.ampproject.org/c/s/www.mercurynews.com/2018/09/10/uc-berkeley-loses-legal-fight-over-crispr-patents/amp/

https://www.nature.com/articles/d41586-018-06656-y

[9] http://www.the-odin.com/diyhumancrispr/

[10] https://www.marketwatch.com/story/sangamo-therapeutics-stock-drops-23-on-results-of-cutting-edge-gene-editing-trial-2018-09-05