How scientists hope to treat diseases by editing our RNA

Opening a new chapter in genetic medicine, scientists have devised a method of gene editing that can turn the protein-production machinery of certain cells on and off at will.

The technique, called RNA REPAIR, could one day treat diseases of the brain, muscles, liver and kidney, whose cells don’t readily yield to DNA-editing techniques such as CRISPR-Cas9.

The RNA REPAIR platform could also prove useful in treating cancer and auto-immune disorders — diseases in which dialing down the action of a given gene for a limited period of time might spell the difference between sickness and health.

The new work, published Wednesday in the journal Science, complements another gene-editing advance reported simultaneously in the journal Nature. That new “base editor” can correct single-letter mutations in DNA without splicing the double helix and causing unintended changes in the genome.

The developments underscore the rapid pace at which scientists have moved from merely describing the sequence of the human genome to manipulating it in fine detail, said Don Conrad, a geneticist at Washington University in St. Louis.

“We can control human biology,” said Conrad, who wasn’t involved in either study.

In the Science paper, molecular biologist Feng Zhang of MIT and the Broad Institute created a wholly new tool for gene editing. Instead of making changes in DNA, it edits the chemical messages in ribonucleic acid, or RNA, which translate DNA’s instructions in every cell into protein production.

That way, it doesn’t effect a permanent change in a cell’s architectural plan; rather, it essentially alters the implementation of that plan.

UC San Diego regenerative medicine specialist Dr. Catriona Jamieson, who was not involved in the new research, called the RNA editor “a really clever approach” to manipulating the genetic underpinnings of human diseases.

Drawing the metaphor of a building, she likened DNA editing to redrafting the architect’s blueprint. Changing the RNA is more akin to having a structural engineer interpret the blueprint, perhaps by adding a beam or a retaining wall to make the overall design work better.

The editing tool itself is made by fusing two naturally occurring proteins. One is an immune-system protein called ADAR, which can repair typos in RNA. The other is Cas13, an enzyme that can cut RNA. It took Zhang and his colleagues close to five years to fine-tune the new system.

The result could someday give doctors the ability to dial up or down a cell’s protein-synthesis machinery for only as long as that adjustment is needed. Once the application of the REPAIR editing tool is suspended, the faithful implementation of cells’ DNA instructions resumes.

Chemical biologist David Liu, the senior author of the base editing report in Nature, called the work of Zheng’s team “an impressive and exciting development” that would offer a complementary approach to permanent gene editing.

For instance, RNA editing could be a “perfect approach” for temporarily turning off the body’s inflammatory response to a disease or therapy, Liu said. Once the danger of an inflammatory spike has passed, withdrawal of the RNA REPAIR tool would allow the immune system’s normal responses to continue unimpeded.

Jamieson said RNA REPAIR could also serve as a temporary block on the activity of certain genes that drive cancer. Even a short-lived disruption might change the course of disease and translate into longer survival, she said.

“Not every change needs to be carved in stone,” she said.

The REPAIR editing tool works by converting the chemical base adenosine to one called inosine at precise spots in RNA’s implementation manual. The unwanted appearance of adenosine in these places is responsible for nearly a quarter of human diseases, Conrad said.

Once the substitution has been made, inosine acts like guanine, the base that should have been there in the first place.

The tool is effective only in cells that don’t divide or replicate beyond the fetal development stage. But such cells — a group that includes neurons, muscle and some liver and kidney cells — account for a significant share of those affected by disease. They are particularly sensitive to chronic injury, toxicity or infection, which can greatly increase the incidence of tumors in these tissues.

As a possible tool for slowing the degeneration of neurons, RNA editing could someday prove useful in treating such diseases as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis, better known as Lou Gehrig’s disease, Jamieson said.

It could happen sooner than scientists once thought possible.

“It’s happened so fast, it’s incredible,” Conrad added. “We’re still years from completing CRISPR-Cas9 trials and have already invented something that could replace it.”