Genetic Engineering & Biotechnology News

DEC 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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GENengnews.com | DECEMBER 2017 | 11 ing, including Feng Zhang, Ph.D., of the Broad Institute, who is currently one of the key patent holders in the CRISPR landscape. The company has a pivotal partnership with CAR-T developer Juno Therapeutics. That deal makes Editas eligible for roughly $700 million in milestone payments through 2020, as well as royalties. Editas is using both Cas9- and Cpf1- based CRISPR systems. Vic Myer, Ph.D., Editas' chief technology officer said the company's first programs are in eye diseases, blood disorders such as sickle cell and beta thalassemia, and improv- ing CAR-T. "Ophthalmic diseases are an attractive starting point for many reasons, including the fact that the eye is a relatively contained, immune–privileged organ," he explained. That makes it less likely there will be systemic side effects. The company aims to file an IND in mid-2018 for Leber Congenital Amaurosis Type 10, which is an inherited form of retinal dystrophy. "We also think gene editing can make CAR-T more durable," he said. "The T cells can adopt a phenotype called 'exhaustion', which makes the therapy less effective, we are working on editing out the signals that trigger that." He adds that solid tumors had also been hard to crack with CAR-T, in part because they have an inhibitory microenvironment. "We are working on editing the T cells to overcome that," Myer said. Jennifer Doudna, Ph.D., was a cofounder of Editas, but split with the group to found a new gene- editing–focused company, Caribou Biosciences. Dr. Doudna is profes- sor of chemistry and molecular and cell biology at UC Berkeley. Caribou Biosciences has spun out several other companies in different fields, includ- ing Intellia Therapeutics, which is also focused on CRISPR/Cas9. The company's initial programs are all in preclinical stages and use lipid nanoparticles to deliver edited genes to the liver. The most advanced of these programs is for transthyretin amyloidosis (ATTR). The company and has some high-profile deals, including one with Regeneron Pharmaceuticals and another with Novartis. "One of Caribou's real advantages is the breadth of tools we have, including our wet lab and computational skills and expertise," said Dr. Haurwitz. The company has, for example, developed its own methodology for measuring off-target effects. The current business model is to focus on collaboration. "We are doing research for others while continuing to improve the platform," she noted. Clearly, CRISPR comes with many caveats. There will likely be seemingly endless patent battles—dis- pute over who is entitled to which of the most important claims is still raging. There are also the off-target effects, the ethical concerns, and the fact that most diseases are not caused by single mutations. And of course, there is the age-old delivery issue that has long dogged related fields, such as antisense and gene therapy. "Sure, you can do it in a dish, but how do you deliver it to particular cells in the body?" asked Joseph Bondy-Denomy, Ph.D., faculty fellow at the University of California, San Francisco. Right now, he pointed out, most companies are targeting the eye, the ear, the liver, and blood cells, which makes sense. But who will push that further? Denomy discovered "anti-CRISPRs" which are proteins that inhibit CRISPR function. He says we still have a lot to learn about CRISPR to optimize the tool. But there is another major question with such a new technology: What are the things that could happen if you "correct" a genetic defect, par- ticularly in a germ cell? As in many other fields, it's possible the biggest stumbling blocks will be the ones we haven't yet anticipated. Still, the race is on, and the rewards could be spec- tacular. haven't even yet realized exist. Still, the race is on and the rewards could be spectacular. B E S T O F C R I S P R 2 017 Caribou Biosciences is among many companies currently racing to get CRISPR-based therapies into the clinic.

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