On a day when the top American intelligence chief called gene editing a potential “weapon of mass destruction,” executives of companies working with CRISPR-Cas9, the most widespread gene editing tool, met to discuss ethical and scientific questions that must be answered before it can be used to treat human disease.
The hurdles haven’t stopped investors from voicing confidence in the companies developing gene editing therapies. Editas Medicine became the first publicly traded company using CRISPR to develop drugs when it held an IPO last week. Cellectis (NASDAQ: CLLS) and Sangamo Biosciences (NASDAQ: SGMO), using different types of gene editing systems, have been public for much longer.
CRISPR-Cas9 is a bacterial defense system being harnessed to edit genes. “CRISPR” is a strand of RNA that guides a particular enzyme, “Cas9,” into a cell’s nucleus to perform genetic surgery. (To date, Cas9 is the enzyme most studied and used, although researchers are exploring CRISPR systems that use other enzymes. For consistency, we will simply use “CRISPR” for the rest of this article.)
A panel discussion Tuesday at the BIO CEO & Investor Conference in New York included representatives from Editas (CEO Katrine Bosley), Intellia Therapeutics (CEO Nessan Bermingham), and Cellectis (CEO Andre Choulika), all joined by New York University bioethics professor Arthur Caplan.
Here are a few takeaways from the talk. (And it should be noted that Editas is still in its post-IPO quiet period, so Bosley could not discuss the company specifically.)
—RNAi and gene therapy as templates, road-pavers. It might feel like the CRISPR hype machine is in overdrive, but the technology is still in its early days. Bosley and Bermingham compared it to the complicated, topsy-turvy development story of two other drug development approaches, RNA interference and gene therapy. “We often use the comparison,” Bosley said, noting the myriad problems that have to be overcome before CRISPR can be put to use as a therapy. “The analogy to RNAi…is a very apt one,” added Bermingham.
RNAi and gene therapy companies have spent years trying to deliver large molecules to the right spot in the body to target diseases. Those viral “vectors,” for gene therapy, for instance, and the locations they’ve been shown to effectively deliver a treatment—like the back of the eye, or the liver—look to be the starting points for the CRISPR companies. Bosley added that earlier types of gene editing technologies, like the zinc finger technology used by Sangamo, had to show promise for CRISPR to be even where it is today.
“It was important that the pioneers for those early genome editing technologies did a good job,” Bosley said. “The whole field is in debt to those folks. They helped pave the path for additional genome editing approaches.”
—Focusing CRISPR’s goals, and other lessons learned from previously hyped technologies. The potential ethical issues with the use of CRISPR have been well-publicized. Fears that the technology might be used to edit the human germline and create “designer” babies and the like spurred an international summit last December, where scientists debated whether specific bans should be placed on the use of CRISPR. “It looks like this is a technology that is [doing something] taboo,” said NYU’s Caplan.
Caplan cited lessons learned from the ethical battles surrounding embryonic stem cells and gene therapy. One of them, he says, is that the goals for CRISPR “are not clear.” Will it be used for therapies? To genetically enhance the human race? Improve quality of life? “The goals have to be very clear, because there’s fear about what this is going to be used for,” he said.
Caplan added that part of the worry with CRISPR, or gene editing more broadly, is that the regulatory framework is also murky. “There’s fear about who’s on the ball, who’s watching it, and how we can shape it to make sure it doesn’t go off the rails,” he said.
—Even with the precedent of gene therapy and RNAi, challenges loom large. No one has any idea what will happen when the first CRISPR drug is given to a human being. That’s part of the reason, Choulika said, that companies “aren’t doing very funky things initially” with where they’re trying to deliver these therapies. They’re thinking places like the eye, or liver, where gene therapies have gone before. (Choulika’s company, Cellectis of Paris, is not using CRISPR. It is using a different gene editing system known in shorthand as TALEN, or transcription activator-like effector nuclease.)
The big scare with CRISPR is off-target cuts; that the molecular scissors snip the wrong part of a person’s DNA and cause unintended effects. Bermingham called this a “very important question” but said CRISPR technology has come a long way. In the first scientific papers, the CRISPR RNA guide—the piece of nucleic acid that is meant to show the molecular scissors where to cut—would not make consistently accurate matches with the target DNA. “There are things learned the last few years that allow us to design very specific guide sequences that are specifically honed to our target of interest,” Bermingham said, although he didn’t provide any details.
—It’s not known what an “effective” CRISPR drug will look like, either. Bermingham noted the CRISPR companies—Editas, Intellia, and the eponymously named CRISPR Therapeutics, based in London—must answer questions for each potential patient group they hope to treat. Which cells need to be edited to get a therapeutic benefit? How many cells need to be edited to create a meaningful effect? How much CRISPR should enter each cell, and how much is too much? “There is no precedent [for that],” Bermingham says.
Even if a benefit is seen in a single dose, will patients need more? Or will CRISPR-based therapies be “one and done”?
All drug makers have to figure out how to fine-tune a drug’s properties for a lasting effect. This has never been done for CRISPR-Cas9 therapies, however. “That is the dialogue that we will be having [in-house] on a program by program basis,” Bosley said.
—The patient variability problem. There can be a number of different genetic subgroups for patients with a specific disease. In the blood disease beta-thalassemia, for instance, about a third of patients are harder to treat because they have two copies of a genetic mutation called b0. Variability like this will present a potential regulatory issue for CRISPR companies. Bermingham said that, in certain diseases, the RNA guide—which is designed to match up, letter by letter, with a specific strand of DNA about 20 letters long—might have to be different for each different genetic subgroup. “And thereby, it’s a different drug,” he said.
Does that mean CRISPR companies would have to conduct rounds of clinical trials for each new RNA guide to come along? What if there aren’t enough patients in some of these genetic subgroups to enroll in clinical trials?
Bermingham said companies like his would likely have to discuss non-traditional drug development plans with regulators.
But there is precedent. Companies like Sarepta Therapeutics (NASDAQ: SRPT) have already been down the development path with their so-called exon skipping drugs for Duchenne muscular dystrophy. (The FDA is expected to decide whether to approve Sarepta’s experimental drug, eteplirsen, by May 26. The prospects for eteplirsen were thrown into question following the release of FDA documents in January that slammed Sarepta’s data.)