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6 CRISPR Applications from Healthcare Startups

One question we’re often asked at Nanalyze is what emerging technology do we think will be most disruptive in the long term. The short answer: All of them. Otherwise, we wouldn’t be devoting long hours at the laptop between trips to the local dispensary writing about all of this amazing progress. Artificial intelligence, as we’ve said before, will be the electricity of the future, underlying all other technologies. Robots will do everything from performing surgery to delivering pizza, while innovative rockets will take us to the moon and beyond. But perhaps one of the biggest game-changers for the human race will be our ability to manipulate life itself through a cutting-edge technique called CRISPR or CRISPR Cas9. CRISPR gene-editing applications range from fighting cancer and infectious disease to discovering diseases and even new drugs.

We’ve written extensively about CRISPR as one of the key developments within gene editing. The clever chaps at data research firm CB Insights have put together a really nice primer on CRISPR, but at its most basic, CRISPR allows scientists to cut and paste genetic code into living organisms, not unlike when you cut and paste text into a Word document. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, which refers to a series of repeating clusters of DNA sequences found in bacterial genetic code to fight viruses. Nearby genes associated with CRISPR are called Cas (CRISPR-associated) genes. What’s so special about these genes is that they create proteins called enzymes that act as molecular scissors that can cut into DNA. An enzyme known as Cas9 is particularly effective at slicing into animal and human DNA. That’s where we get the term CRISPR Cas9.

How CRISPR Cas9 works.

How CRISPR Cas9 works. Credit: CB Insights

As we’ve written before, there are currently three pure-play stocks out there for gene editing using CRISPR technology: Editas Medicine (NASDAQ:EDIT), Intellia Therapeutics (NASDAQ:NTLA) and CRISPR Therapeutics (NASDAQ:CRSP). Our most recent update on gene editing found the trio still embroiled in patent wars over the technology. Generally speaking, the edge in the United States goes to Editas, while Intellia and CRISPR Therapeutics (whose respective founders are collaborators) are having more success in European courts. Still, there are plenty of patents to go around: The U.S. Patent and Trademark Office has issued more than 60 patents with claims to CRISPR and/or Cas9 to about 100 inventors from 18 applicant organizations. The European Patent Office has issued more than 20 patents to around 30 inventors from about ten applicant institutions.

In other words, despite the patent wars, there’s no lack of CRISPR applications and startups that are trying to exploit them. In the rest of the article, we highlight six CRISPR applications and some of the top-funded startups (via CrunchBase) that are hoping to commercialize these technologies in healthcare.

CRISPR for Cancer Treatment

One of the leading CRISPR applications is for cancer treatment. On one end, CRISPR can be used to study the effects of cancer by replacing a normal gene with a nasty cancer version to watch how it unfolds, like inviting your alcoholic uncle to your daughter’s 16th birthday party. Other scientists are experimenting with CRISPR to create new cancer immunotherapy treatments by engineering immune cells, or T-cells, to kill cancer cells.

CRISPR for Cancer Drug Screening

Click to go to company websiteFounded in 2016, Repare Therapeutics out of Montreal announced a $68 million Series A in June 2017, officially emerging out of stealth mode. Investors include Celgene (NASDAQ:CELG), a $64 billion biotechnology company that specializes in cancer treatments, so they probably know talent when they see it. The startup is applying the money toward its CRISPR-enabled synthetic lethality drug discovery platform, which is quite a mouthful. At the core of Repare’s platform is the idea that a tumor can tolerate individual defects in its DNA, but will be destroyed by combinations of mutations or defects, like U2’s last album, Songs of Innocence. CRISPR Cas9 is used to create cancer variations at scale in order to screen for the right combo of drug and mutation that will destroy bad cells while leaving the good ones alone.

Repare Therapeutic's CRISPR-enabled synthetic lethality drug discovery platform.

Repare Therapeutic’s CRISPR-enabled synthetic lethality drug discovery platform. Credit: Repare Therapeutics

Click to go to company websiteOfficially launched with a $55 million investment last year from Boston-based Third Rock Ventures, Tango Therapeutics in Cambridge is also developing a CRISPR-enabled synthetic lethality drug discovery platform. The concept of synthetic lethality has been previously proven using a class of drugs called PARP inhibitors, which block an enzyme that cancer cells with specific mutations use to repair themselves. Tango’s founder, Alan Ashworth, just happens to be the guy who figured all that out. We can’t figure out how to use Roku to stream Netflix without using YouTube tutorials.  

CRISPR for Cancer Cell Treatment

Click to go to company websiteFounded in 2015, Refuge Biotechnologies is a Silicon Valley startup that took in $25 million from Sequoia China and a number of other investors from the PRC, some of whom get exclusive rights to commercialize the company’s cell therapy technologies in China. Refuge doesn’t use CRISPR to edit genes but to control them. Refuge co-founder Stanley Qi mutated the Cas9 protein so that it can no longer cut DNA, creating a “dead Cas9” or dCas9. It was far from a dead end, however, as dCas9 can switch genes off (CRISPRi, for interfence) or on CRISPRa, for activation). That allows the company to deliver multiple therapies to a single cell using dCas9.

The drug pipeline from Refuge Biotechnologies.

The drug pipeline from Refuge Biotechnologies. Credit: Refuge Biotechnologies

The company’s lead candidate is RB-1916, a cell therapy designed to inhibit the expression of a particular gene associated with diffused large B-cell lymphoma.

CRISPR for Disease Detection

Click to go to company websiteFounded in 2017, Mammoth Biosciences has raised $23.1 million in disclosed funding, most of it in July. The company (co-founded by Jennifer Doudna, one of the leading CRISPR researchers and head of Intellia Therapeutics) is leveraging CRISPR-based technology out of the University of California, Berkeley, that promises to detect any biomarker or disease containing DNA or RNA. The 30-minute test only requires a credit card-sized test strip and a smartphone for simultaneous detection of multiple conditions. It sounds like something out of the playbook of Theranos, the disgraced health company that claimed it could detect hundreds of diseases from a drop of blood, but only ended up squeezing $700 million in blood money out of investors.

But with a name like Doudna behind Mammoth Biosciences, we suspect this is the real deal. It’s also based on some sound science, employing two CRISPR proteins that enable the Mammoth platform to detect virtually any type of nucleic acid. Both are programmable by a molecule called a guide RNA, which allows the system to be used in any application that contains a DNA or RNA component, meaning it has uses in many industries outside of healthcare. Stay tuned.

CRISPR for Treating Genetic Disease

Click to go to company websiteFounded in 2017, Beam Therapeutics is another startup out of Cambridge that has amassed $87 million this year, probably thanks to some big names behind the company, including Feng Zhang, founder of Editas. The cash will help the startup develop precision genetic medicines that make edits to individual base pairs in the genetic code. DNA is made up of billions of nucleobases, or bases, each represented by a single letter (A, G, T, C), just like in Sesame Street (except completely different). These bases are then encoded in RNA messages for expression by the cell. Base editors are capable of precisely targeting and editing just one base out of billions within the genome, without cutting the DNA or RNA.

Beam Therapeutics can precisely repair a variety of disease-causing mutations, write in beneficial genetic variations known to protect against disease, or modulate expression of disease-causing genes.

Beam Therapeutics can precisely repair a variety of disease-causing mutations, write in beneficial genetic variations known to protect against disease, or modulate expression of disease-causing genes. Credit: Beam Therapeutics

Why is all that important? It turns out that more than half of genetic errors associated with genetic disease result from a single letter change in the billions of bases that make up the genome. It’s not just about preventing disease: Certain genetic variations in DNA can also protect someone against a disease by simply changing one letter in the alphabet soup of our DNA.

CRISPR for Treating Infectious Disease

Click to go to company websiteWe head south to Raleigh, North Carolina, where Locus Biosciences has raised $26 million, wrapping up the extended Series A in July. Remember that CRISPR is based on how bacterial DNA operates. Keeping that in mind, Locus (founded in 2015) is developing therapies that create “smart bombs” based on CRISPR technology that kill antibiotic-resistant superbugs by irreversibly destroying the bacterial DNA. It’s basically repurposing the bacteria’s immune system against viruses to kill it.

Locus Biosciences' antibiotic product platform.

Locus Biosciences’ antibiotic product platform. Credit: Locus Biosciences

In this case, the startup is using the CRISPR Cas3 enzyme to destroy pathogens such as Clostridium difficile, which can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon. Another bad bacteria in Locus’ crosshairs is Pseudomonas aeruginosa, known for its antibiotic resistance related to serious illnesses like sepsis and pneumonia.

CRISPR for Treating HIV

Click to go to company websiteFounded in 2015, Philadelphia-based Excision BioTherapeutics raised a $10 million Seed round last year to begin clinical trials in a test of its ViraSuite CRISPR platform for eradicating life-threatening, viral-related diseases. First up is HIV-1. Excision does exactly what its name implies, removing or excising the HIV-1 genome from a patient’s cells and tissues. The startup says its unique computational approach allows for more intensive focus, resulting in getting therapies into a clinical setting in just two to three years, far more quickly than normal:

The drug pipeline from Excision BioTherapeutics.

The drug pipeline from Excision BioTherapeutics. Credit: Excision BioTherapeutics

The company also recently licensed new CRISPR Cas9 technology based on work involving Intellia’s Doudna.

Conclusion

So, as you can imagine, while there are many applications for CRISPR, the number of people actually working on this emerging life-saving technology is still relatively small and pretty incestuous. You can imagine the current structure as a family tree, with Editas Medicine, Intellia Therapeutics and CRISPR Therapeutics forming the trunk of a sapling that seems to be growing rapidly. It just needs a little sunshine and VC dollars to keep growing.

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