The newest gene editor radically improves on CRISPR

NCER Notes:

Research has shown that the CRISPR gene editing tool (which cuts out and replaces diseased DNA) holds great potential for healing disease, but currently poses a significant risk to humans due to frequent unintended mistakes, or “off-target” mutations in DNA. A solution is being pursued, but in the meantime, a new kind of gene editing, called “Prime Editing” has just been announced this week. Prime Editing uses much of CRISPR technology, but appears to improve it, offering a safer, more reliable process because it edits DNA without ever actually cutting it, thereby removing the risk of mistakes (harmful mutations). If this Prime Editing proves safe and effective in future human trials, it could literally eradicate human diseases. The ethical use of any gene editing technology would include 1) use in adults or children (not egg, sperm or embryos), and would require 2) informed consent, 3) benefits that outweigh the risks, 4) fair availability to all.

Researchers have developed “prime editing,” a true search-and-replace function for DNA.

Oct 21, 2019

For all its well-earned fame, the gene-editing tool CRISPR is, in reality, pretty hard on the genome. It’s a pair of DNA scissors that cuts the double helix, and what’s called “editing” is actually a cell’s hasty attempt to patch things back together. That introduces errors: critics have even called these unpredictable changes a form of “genome vandalism.”

So researchers are searching for ways to make CRISPR live up to its reputation as a real search-and-replace function for genes. In the words of David Liu, a Harvard University biologist, the ultimate aspiration of genome engineers is “the ability to make virtually any targeted change in the genome of any living cell or organism.”

Today, in the latest—and possibly most important—of recent improvements to CRISPR technology, Liu is introducing “prime editing,” a molecular gadget he says can rewrite any type of genetic error without actually severing the DNA strand, as CRISPR does.

The new technology uses an engineered protein that, according to a report by Liu and 10 others today in the journal Nature, can transform any single DNA letter into any other, as well as add or delete longer stretches. In fact, Liu claims it’s capable of repairing nearly any of the 75,000 known mutations that cause inherited disease in humans.

CRISPR 1.0 is harnessed most often to disable genes—making it useful for research and possibly in treating a subset of diseases where a DNA delete button is what’s called for. More extensive gene replacements are also possible with this tool but aren’t easy to control.  

The new technology, which delivers a wider menu of edits with more finesse, is already worth untold sums of money. Even before the paper was published, a syndicate of venture capitalists, including Newpath, Google’s venture arm, and F-Prime, had formed a company, Prime Medicine, and bought rights to it from the Broad Institute, where Liu has a lab.

The company is very new—no location yet, no employees—so we’ll have to wait to learn if it’s going to be the latest to try to develop CRISPR drugs or will do something else. Robert Nelsen, a partner at Arch Venture Partners, a fund also involved in the deal, emailed to say he couldn’t offer more detail. “Amazing time in the scientific world,” he wrote. “We are not saying anything at this time.”

How does prime editing work?

It is a type of CRISPR because it employs the same bacterial miracle protein, Cas9, which can zero in on a predetermined location in a plant or animal genome, finding its way among billions of letters. But unlike CRISPR classic, prime editing doesn’t break the DNA helix.

Liu and his group kept the part of Cas9 that serves as a homing mechanism but removed the scissors part—a component called a nuclease. In its place they spliced another enzyme, reverse transcriptase, well known in biology textbooks because it’s what chugs along your chromosomes when your cells divide, spooling out a new copy.

A document editor really is the right image if you want to picture how Liu’s new engineered molecule works. First, researchers add a bit of genetic text they want to put into a genome (think of that as the “copy” command). Cas9 then acts like the cursor, finding the right position in the DNA. Last, reverse transcriptase acts like a “paste” command, copying in the genetic text prepared by the scientists.

Liu’s team, including postdoc Andrew Anzalone, tried prime editing on cells in their lab. They say they fixed the error that causes sickle-cell disease (one wrong letter), the one that leads to Tay-Sachs disease (four extra letters), and a mutation that’s a common cause of cystic fibrosis (three missing letters).

The original CRISPR can be made to do some of these tricks too, but with low odds of accurate results, which is why for the last several years Liu’s lab had been trying to extend the technology’s abilities.  An earlier invention, base editing, allowed them to transmute certain individual DNA letters into others. Yet not every type of change was possible. Prime editing, they say, could conceivably repair most inherited DNA errors found in the human species that causes genetic disease.

The big sums involved in the scramble to commercialize editing super-tools is evident in the IPO plans of Beam Therapeutics, a separate company Liu founded to work on base editing, which has helped advance prime editing too. The Harvard researcher’s financial stake in that gene-editing startup, which is aiming to treat blood diseases like sickle-cell, is expected to be worth more than $50 million when Beam goes public.

The promise to potentially resolve the entire spectrum of inherited human ailments is huge, but in practice it’s still distant. Editing tools are not like aspirin, a small molecule that slips easily into cells. The prime editor is, in molecular terms, gigantic—so getting it into people’s cells is going to require something like gene therapy. 

The research was paid for by the government and philanthropists and carried out at Harvard and the nonprofit Broad Institute. The system will be made available for just a few dollars through a clearinghouse, Addgene, to anyone who wants to use it for basic science.

Since CRISPR 1.0, base editing, and prime editing each have some pros and cons, Liu expects all to remain in use. With prime editing, not every cell takes up the wanted change—meaning that it’s not yet as efficient as researchers would like.

“This is the beginning rather than the end,” Liu told journalists in a conference call arranged by Nature. “If CRISPR is like scissors, base editors are like a pencil.  Then you can think of prime editors like a word processor, capable of precise search and replace … All will have roles.”

As genome editing becomes more potent, controversies around certain potential uses—say, to make designer babies, genetic pesticides, or even bioterror weapons—are likely to be sharpened.

Liu didn’t reply to questions about whether the powerful new tool has any downsides or how financial incentives are shaping the choice to create, and widely share, these means of changing the molecule all life is based on.

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