Gene Editing Execs Talk Scientific, Regulatory Hurdles At BIO Panel

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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.)

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