What’s happening with CRISPR these days? Another company just filed for an IPO, documents relevant to CRISPR patent war have come to light, research is moving forward, and the therapy is one step closer to the clinic. In this review, we discuss why the exciting new technology and the drama surrounding it: big money, no clinical results and a ton of patent hostility.

By this point, you can’t have escaped hearing about CRISPR. First discovered in the 1980’s, the repeated sequences and their function in bacterial defense systems remained a mystery until almost 10 years ago, when it was hailed as the biggest scientific discovery of the century. Since then, scientists have leveraged the adaptable, heritable mechanism to develop the most powerful gene-editing technology to date, known as CRISPR-Cas9.

How does the ‘DNA Scissors’ Work?

There are three major parts to this system: the cutting enzyme, Cas9; guide RNA, to guide Cas9; and the DNA to be cut. The guide RNA is able to direct Cas9 by having a specific sequence, in this case the repeat that gives CRISPR its name, which complements a portion of the target DNA.

These strands combine, and Cas9 goes to work, cutting both strands of the DNA, implanting new DNA, and stitching it back together. Cas9 can also be modified with the addition of a protein to activate or repress specific genes.

crispr-fig1

crispr-fig2

Figure 1. CRISPR’s mechanism of action

The genetic repeats of the guide RNA give CRISPR its name: it stands for Clustered Regularly Interspaced Short Palindromic Repeats of DNA, and these sequences come from the DNA of viruses. Bacteria extract a virus’s DNA after fighting it off; the bacteria then integrate that DNA into its own genome as a spacer using a nuclease, most commonly Cas9.

This is a highly specific tunable mechanism, as the enzyme targets specific motifs on either side of the viral DNA using own strand of RNA (crRNA). Scientists have since developed it into a revolutionary technology to edit the human genome.

RadioLab has a pretty sweet podcast on the evolutionary origins of CRISPR if you want to hear more.

Up until this point, the only competing editing technologies were zinc fingers and TALEN enzymes, both of which require the labour-intensive generation of entire proteins. (That said, TALEN has since been developed into a more precise tool that has made it to clinical trials.)

While improvements need to be made in its specificity, CRISPR-Cas9 is easier to manipulate as an RNA-based technique and therefore much simpler and faster than either of its predecessors. This improvement is crucial for high throughput gene editing tests to adapt treatments quickly to fit the needs of a patient.

Who’s Who in the CRISPR Biotech Space

There are three horses in the race to bring a CRISPR therapy to market: Editas, Intellia Therapeutics, and CRISPR Therapeutics.

While at UC Berkeley, Jennifer Doudna reported the origins of CRISPR-Cas9 and later developed it into a tool to edit the human genome with Emmanuelle Charpentier, now the Director of the Max Planck Institute for Infection Biology in Berlin and notably absent from the patent battlefield. In 2012, Charpentier co-founded CRISPR Therapeutics, a Boston-Basel operation initially funded by Versant Ventures, with Rodger Novak (check out what he had to say at our conference in May!) and Shaun Foy.

Figure 2. Artistic interpretation of a battle between bacteria and viruses.

Prior to that, however, Doudna founded Editas, which focuses on correcting genetic blindness as a proof of concept, with Feng Zhang of the Broad Institute and George Church of Harvard Medical School in 2013. Zhang, in collaboration with Church, was actually the first to publish the use of CRISPR-Cas9 to edit human DNA in January 2013; Doudna’s own demonstration was published a few weeks later.

Zhang now claims credit for the CRISPR gene editing technology, citing his graduate students’ laboratory notebooks; this drove Doudna to cut ties officially in 2015, when she and her company, Caribou Biosciences, joined Intellia Therapeutics as founders.

Figure 2. From left to right, Jennifer Doudna, Emmanuelle Charpentier, & Feng Zang.

Figure 3. From left to right, Jennifer Doudna, Emmanuelle Charpentier, & Feng Zang.

Intellia Therapeutics is the third competitor in the race to develop some kind of CRISPR-based therapy. It has a number of programs targeting CAR-T Cells, internal metabolism errors and Hepatitis B, among others. The year after it was founded in 2014, it partnered with Novartis, the world leader in CAR-T cell therapy, to develop its own CAR-T and HSC programs.

Since Editas and Intellia made initial public offerings (IPO’s) earlier this year, the companies’ values have skyrocketed to almost €1B each. CRISPR Therapeutics, which has set up shop on Kendall Square in Boston next to its competitors, has just filed for an IPO of €80M, though this figure may be a conservative estimate.

Patent War Breaks Out

The CRISPR-Cas9 system was of immediate interest to biotech for its vast potential to cure genetic diseases, and patent ownership of CRISPR will be crucial for further development. Berkeley (Doudna) and the Broad (Zhang) are currently duking it out for the patent to claim intellectual property and the lion’s share of revenue from future therapies.  So far, Editas has paid almost €9M to defend its title as principal owner.

We’ve summarized the major battles in this handy infographic:

screen-shot-2016-09-13-at-09-26-58

So far, Zhang is winning: in 2014, the US Patent and Trade Office awarded him a patent for use of the technology in eukaryotes (any organism whose cells have nuclei), which obviously has a very broad reach. Doudna filed a patent application earlier than Zhang, but the Broad paid a substantial fee to have his fast-tracked.

For now, it appears to have paid off, but the dispute is far from over: Doudna initiated an interference proceeding in April 2015, which, if she wins, entitles her to take over their patent. We’re waiting with bated breath for updates on the process.

Where are we now?

Just because CRISPR-Cas9 doesn’t have an unassailable intellectual owner yet doesn’t mean research on it has stopped: if this all wasn’t enough excitement for you, academia is plowing ahead with development. Church has assembled a team of 30 people to improve it in an attempt to outflank the current competition. Zhang has since discovered another cutting enzyme, Cpf1, and Charpentier is moving forward with its development.

Among the three main competitors we’ve discussed, Editas is currently leading the race to the clinic with clinical trials slated to start in 2017. While these companies were wrestling with the ethical implications of CRISPR, a Chinese company seized the lead in human development by editing embryos and then starting the first clinical trials of a CRISPR-based lung cancer therapy.

Figure 3. And where are the companies? In Boston, of course!

Figure 4. And where are the companies? In Boston, of course!

The established companies have collected around €100M each in fundraising rounds, and CRISPR Therapeutics just increased its Series B to a whopping €125M. Subsidiaries of patent holders are quickly establishing themselves (Casebia most recently), and others are others like Desktop Genetics are occupying the bioinformatic space around CRISPR. These are massive investments on potentiall risky projects, given that none of the companies’ CRISPR therapies have yet reached the clinic.

A team at UPenn has turned up the heat in the race, when it attained the first NIH approval of a CRISPR trial in June! It plans to use CRISPR-Cas9 to insert a gene to better detect cancer cells and suppress a gene expressing biomarkers on T-cells that are blocked by cancer cells. It still needs FDA approval, but this is a huge step closer to the market.

That’s not all, folks

For all of its promise, CRISPR gene editing technology has been hailed as the biggest discovery of the century, and we’re sure it will eventually win its developer(s) a Nobel Prize. But who will take home the title? The ongoing patent dispute has been getting messier as more information comes to light: Zhang and the Broad won the last battle, but Doudna and Berkeley are launching a counter attack.

Meanwhile, research continues to refine the technique with the goal of bringing it to market. So far, none of the players in the patent war have any clinical data! But that hasn’t stopped investors from plying CRISPR companies with money, making them some of the best funded in the industry.

The games have only just begun: look out for news on the first clinical trials, CRISPR Therapeutics’ IPO and developments in the patent war!


Reference: The CRISPR Craze, Elizabeth Pennisi, 2013. Science 341 no. 6148 pp. 833-836
Featured Image: Collage by author –  Scissors (CC2.0, Kevin Doncaster/Flickr), DNA? (CC2.0, Thomas Wensing/Flickr)
Figure 1: The CRISPR Craze, Elizabeth Pennisi, 2013. Science 341 no. 6148 pp. 833-836
Figure 2: Wu Jian’an detail May 2012 White Rabbit Gallery (CC2.0, Melanie Lazarow/Flickr)
Figure 3: Jennifer Doudna (CC2.0, KNAW/Flickr), Max Planck Institute for Infection Biology, Massachusetts Institute of Technology
Figure 4: Boston à l’heure bleue (CC2.0, Emmanuel Huybrechts/Flickr)

Previous post

Celyad's unique CAR-T approach is ready for Efficacy Studies

Next post

Horizon Pharma successfully negotiates Acquisition of US Competitor for €712M