MIT scientists invent technology to replace defective genes or upload new ones

“This is a huge innovation,” said Maura McGrail, a biologist who uses gene editing to study brain development and disease in animal models at Iowa State University. “It really opens up the possibility for us to modify the genome in a way that can be useful for both biomedical research and gene therapy.”

Such treatments are at least a few years away from being tested in humans. So far, the technology has only been tested on human cells grown in a Petri dish and on laboratory mice.

But biotech investors have already lined up to get involved in the technology and related approaches. Cambridge-based Prime Medicine, Somerville-based Tessera Therapeutics and Watertown-based Tome Biosciences — founded last year by Abudayyeh and Gootenberg — are all working on technologies aimed at adding new genes or replacing faulty ones to treat diseases .

These companies and others in earlier stages are developing a third generation of technologies based on CRISPR gene editing – the revolutionary tool invented just over a decade ago that enabled biologists to manipulate DNA easily and precisely. Several Boston-based companies are testing experimental therapies based on previous generations of CRISPR in clinical trials.

The first generation of CRISPR tools relied on a bacterial enzyme called Cas9 to cut DNA at specific locations in the genome, a method that can turn off disease-causing genes. Scientists can also use Cas9 to create an opening for a new gene, but this approach is inefficient and tends to introduce unwanted and potentially dangerous mutations.

A second generation of tools, known as basic editors, can swap out a single letter in the genetic code for another, which can correct typos responsible for inherited diseases. But many diseases are caused by several different genetic mutations, and it is unrealistic to develop basic therapies for all.

Third-generation gene editing promises to overcome these limitations with tools and techniques that can target a variety of diseases more safely and efficiently. The methods have many names. Prime calls it Prime Editing, Tessera calls it Gene Writing, and Tome calls it Gene Insertion. All of them use complex molecular machines composed of natural enzymes that are tweaked and assembled to add or replace DNA at precise locations in the human genome.

“We now have multiple technologies to solve a problem that didn’t have solutions not long ago,” said Marc Güell, a synthetic biologist at Pompeu Fabra University in Spain who co-founded Integra Therapeutics in Barcelona to develop his own gene writing technology. Harvard University geneticist George Church is a member of the startup’s Scientific Advisory Board.

The field is quickly becoming one of the most competitive and secretive sectors of the biotech industry. Experts say many of these gene-writing technologies share similarities, but since many of the companies are reluctant to go into the details of their approaches, it’s difficult to make direct comparisons.

Tome, the company founded by Abudayyeh and Gootenberg, is developing “programmable gene insertion,” a language that mirrors PASTE’s description, according to its website. But Abudayyeh and Gootenberg declined to confirm that Tome is using the technology, and the company did not respond to a request for comment.

The newly published study shows that a core part of the PASTE technology is an enzyme called integrase, which some viruses use to insert their own genes into bacteria. In nature, these enzymes only insert viral genes at specific stretches of DNA that act like molecular landing pads. This limitation has made it difficult for scientists to reuse integrases as a tool to insert genes into human genomes.

Abudayyeh and Gootenberg tried to solve this problem by combining the integrase with two other enzymes that work together to create a landing pad for the integrase at the exact spot in the genome where the researchers want to insert the piece of therapeutic DNA.

“It’s impressive work, no question about it,” said Erik Sontheimer, gene editing researcher and vice chair of the RNA Therapeutics Institute at UMass Chan Medical School. New methods for precisely inserting DNA into the genome are “something everyone wants,” he added. Sontheimer is on the scientific advisory board of Tessera.

Two of the three enzymes used in the PASTE technique are the same ones used in the prime editing technique developed by David Liu, a researcher at the Broad Institute of MIT and Harvard, which uses tens to hundreds of letters of the DNA Codes can be added into a genome.

Some researchers told the Globe that PASTE is essentially a new iteration of Prime editing and not an entirely new technology. Abudayyeh and Gootenberg acknowledged that PASTE is built on top-notch editing, but stressed that it took a lot of engineering to get all three enzymes to work together. They also said their approach can be used to add much larger pieces of DNA — up to 36,000 letters long — than Prime editing.

But the PASTE technique was only 2.5 percent effective at integrating a new gene into liver cells in mice. Sontheimer said that means there’s plenty of room for improvement, but noted that other gene-editing technologies have also been introduced with low success rates and have since improved.

“This is just the first try,” he said. “Once you’ve established your baseline, tweak, tweak, tweak as many knobs as you possibly can access, and those numbers go up.”

Ryan Cross can be reached at [email protected] Follow him on Twitter @RLCscienceboss.


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