Scientists Use New Crispr System to Edit RNA in Human Cells
Scientists Use New Crispr System to Edit RNA in Human
Cells
Feng Zhang, the senior author on the paper, says he
believes that Cas9 and Cas13 are ‘only the tip of the iceberg.’
Targeting ribonucleic acid carries potentially fewer
scientific and ethical risks than editing DNA
By Amy Dockser Marcus Oct. 25, 2017 1:37 p.m. ET
Researchers said they created a new Crispr-based system
to edit RNA instead of DNA in human cells, offering a way around some of the
ethical and scientific challenges associated with editing the genome and
helping advance a new avenue to potentially treat diseases.
Scientists at the Broad Institute of MIT and Harvard
repurposed the Cas13 enzyme in the Crispr system to target and correct
disease-causing mutations in RNA in cells. The new RNA-editing system, which
the scientists have dubbed Repair, allows the editing of individual RNA
letters, correcting a common mutation known to play a role in a number of
diseases. They described their research in a paper published in Science Wednesday.
Crispr, which stands for clustered regularly interspaced
short palindromic repeats, serves as the immune system of bacteria and is used
to defend against viral attacks.
RNA, or ribonucleic acid, is a molecule and is found in
all cells. It serves as a messenger, carrying the DNA’s instructions to the
cells for making the proteins that are essential for life. Scientists have long
believed RNA to be a good therapeutic target, but initial work using the Crispr
system has focused on another enzyme, Cas9, and on making edits in DNA, which
cause permanent changes to a person’s genome.
Unlike with DNA, cells constantly produce more RNA. As a
result, RNA editing carries potentially fewer scientific and ethical risks. For
one thing, if “off-target” changes occur, a key area of concern in editing DNA,
the RNA edits are potentially reversible. Understanding of the biology of many
diseases is also rapidly changing, and RNA editing allows scientists to more
easily revise the therapy as more research is done.
“Crispr editing of RNA creates more opportunities for
things we can do therapeutically,” says Elizabeth McNally, director of the
Center for Genetic Medicine at Northwestern University’s Feinberg School of
Medicine, who wasn’t involved in the study but is working on efforts to use the
Crispr system to treat forms of muscular dystrophy and other conditions.
Scientists have been looking for ways to modulate RNA in
order to treat diseases. Last month, Alnylam Pharmaceuticals , which said it
spent 15 years developing its therapy, reported positive results in a trial of
a so-called RNA-interference drug, patisiran, which stops production of a
disease-causing protein to treat a rare nerve disorder, familial amyloid
polyneuropathy. If approved by the Food and Drug Administration, patisiran
would be the first commercial product based on RNA interference.
Crispr offers another approach.
In nature, there are many different Cas13 enzymes that
bacteria use to target and cut RNA as part of its defense system. Omar
Abudayyeh, one of the co-first authors of the Science paper, said the
researchers spent more than 18 months studying different Cas13 enzymes to find
the most effective to adapt for RNA editing in human cells.
The scientists eventually chose a Cas13 enzyme from the
Prevotella bacteria, then combined it with a protein called ADAR2. The Cas13
enzyme targets the desired spot on the RNA, and the ADAR2 protein corrects the
disease-causing mutation by changing individual RNA letters, in this case
adenosines to inosines.
No cutting is done, avoiding the problem of figuring out
how to get the cell to make a proper repair, among the challenges faced when
using Crispr systems to cut DNA.
To test whether Repair works, in the lab the researchers
created the mutations that lead to two diseases, Fanconi anemia and X-linked
nephrogenic diabetes insipidus, introduced the mutations in human cells, and
used the Crispr-based Repair system to correct the RNA. The scientists say they
are working to adapt the system to do other letter corrections.
Feng Zhang, the senior author on the paper, says he
believes that Cas9 and Cas13 are “only the tip of the iceberg. There are likely
many more Crispr systems to be discovered that will have therapeutic
applications.”
Gene Yeo of the University of California San Diego, who
led a team that published a paper earlier this year adapting the Cas9 Crispr
enzyme to edit RNA and set up a company to try to bring RNA editing into
clinical trials, says researchers still need to overcome a number of hurdles
before RNA editing is used in people. For one they must ensure that RNA edits
don’t trigger an adverse response by the body’s immune system.
But he says when it comes to developing Crispr
therapeutics to treat human diseases, “editing RNA may be more therapeutically
amenable than editing DNA.”
Write to Amy Dockser Marcus at amy.marcus@wsj.com
Appeared in the October 26, 2017, print edition as
'Researchers Sidestep the Editing of DNA Targeting ribonucleic acid may raise
fewer scientific and ethical risks than editing DNA.'
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