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CHRISTOPH BURGSTEDT/SPL

Tools to edit messenger RNA (artist’s illustration) are said to be safer than the CRISPR–Cas9 system, which changes the genome itself.

MOVE OVER, CRISPR:

RNA-EDITING THERAPIES
PICK UP STEAM
Two RNA-editing therapies for genetic diseases have in the past few months
gained approval for clinical trials, raising hopes for safer treatments.

By Mariana Lenharo

R
NA editing is gaining momentum.
After decades of basic research into
how to alter this complex molecule,
at least three therapies based on RNA
editing have either entered clinical
trials or received approval to do so. They are
the first to reach this milestone.
Proponents of RNA editing have long argued
that it could be a safer, more flexible alterna-
tive to genome-editing techniques such as
CRISPR, but it poses substantial technical
problems. The launch of human trials signals
the growing maturity and acceptance of the
field, scientists say. “There’s a much greater
understanding of RNA technology, and that’s
been partially enhanced by the RNA vaccine
and the COVID pandemic,” says Andrew Lever,
a biologist at the University of Cambridge,
UK. “RNA is now seen as a very important
therapeutic molecule.”
Temp job
RNA has a key role in protein synthesis: the
genetic information encoded in DNA is tran-
scribed into messenger RNA (mRNA) and then
translated into proteins. RNA molecules are
composed of units called nucleotides, each
containing one of four bases, or letters.
RNA-editing techniques aim to compen-
sate for harmful mutations by changing the
sequence of RNA, allowing normal proteins to
be synthesized. RNA editing can also increase
the production of beneficial proteins.
Unlike CRISPR genome editing, RNA editing
doesn’t change genes. Nor does it introduce
permanent changes, because RNA molecules
are transient. This means that the duration of
the therapeutic effect could be shorter.
But that transience could offer safety
advantages. One risk of CRISPR therapies
is off-target effects, or unintended changes
outside the target genomic region, notes
Joshua Rosenthal, a neurobiologist at the

Nature | Vol 626 | 29 February 2024 | 933

News in focus
Marine Biological Laboratory in Woods Hole,
Massachusetts. “An off-target effect in DNA is
potentially quite dangerous. In RNA, it’s less
so, because it’s going to turn over.”
One letter at a time
One common RNA-editing approach, single-
base editing, harnesses an enzyme that is
already found in cells: adenosine deaminase
acting on RNA (ADAR). This enzyme swaps a
base called adenine in the RNA sequence for
a base called an inosine.
Wave Life Sciences in Cambridge, Massachu-
setts, is exploring single-base editing to treat
a genetic disorder called alpha-1 antitrypsin
deficiency (AATD), which can damage the
lungs and the liver. The disease reduces the
production of AAT, a protein made in liver cells
that protects lungs from damage caused by
inhaling polluted air or other irritants.
Wave’s product is a short chain of nucleo-
tides that directs naturally occurring ADAR
enzymes to change a specific letter in each
mRNA molecule to correct the mutation that
affects AAT production. “By using the cell’s
endogenous machinery to edit that single
base, you now make a normal protein. And
we’ve shown that the normal protein can be
expressed at high levels,” says Paul Bolno,
Wave’s president and chief executive.
In mice, the drug edited around 50% of the
target mRNA in liver cells, which is enough to
produce therapeutic effects, Bolno says.
The company’s clinical trial of the drug
began last December in the United Kingdom
and Australia, and will evaluate the drug’s
safety and other features.
Editing whole paragraphs
Another approach, called RNA exon editing,
changes thousands of genetic letters in an
RNA molecule at once, as opposed to changing
just one letter. Exon editing is akin to editing
a whole paragraph instead of correcting one
typo, says Lever. This technology is particu-
larly important for disorders caused by mul-
tiple mutations in a person’s genome; such
arrays of mutations are difficult to address
with single-base changes, he adds.
The technique targets pre-mRNA, which
is transcribed from DNA and then processed
to make mRNA. Pre-mRNA includes both
exons — parts of the RNA transcript that con-
tain instructions for making proteins — and
introns, which don’t contain such instructions.
Through a mechanism called RNA splicing, the
introns are cut out of the pre-mRNA, and the
exons are stitched together to form the final
mRNA, which is translated into protein.
Companies such as Ascidian Therapeutics
in Boston, Massachusetts, are leveraging
the RNA-splicing process to remove muta-
tion-containing exons and replace them
with healthy ones. Last month, Ascidian
received approval from the US Food and Drug
934 | Nature | Vol 626 | 29 February 2024
Administration for a clinical trial of an exon
editor to treat Stargardt disease, which causes
vision loss. People with the disease have sev-
eral mutations in a single gene, leading to the
production of a defective version of a protein
that usually protects the retina.
Ascidian’s therapy relies on an engineered
DNA segment that is delivered into cells and
produces normal RNA exons. These replace
“RNA is now seen as
a very important
therapeutic molecule.”
the mutated ones during the splicing process,
resulting in functional proteins. The DNA also
produces RNA sequences that facilitate exon
editing.
“With one molecule, [the therapy] is able to
replace 22 exons at one time,” says biologist
Robert Bell, head of research at Ascidian.
Cancer-quashing RNA
The potential of RNA-based therapies is not
limited to genetic diseases. Rznomics, a bio-
pharmaceutical company in Seongnam, South
WHY VOLUNTEERS WILL
GATHER DNA FROM
HUNDREDS OF LAKES
Massive environmental DNA project aims to take a
record-setting snapshot of biodiversity worldwide.
By Lydia Larsen
I
n a first-of-its-kind project, researchers are
tapping into the power of citizen science to
collect DNA samples from hundreds of lakes
around the world. Not only will the resulting
cache of environmental DNA (eDNA) be the
largest ever gathered from an aquatic setting in
a single day — it could also yield a fuller picture
of the state of biodiversity around the globe
and improve scientists’ understanding of how
species move about over time.
Scientists are increasingly using eDNA —
which is shed by all organisms — to evaluate
the presence of species in a given environ-
ment. Researchers have shown that it can be
cheaply and efficiently extracted from water1,
soil2, ice cores3 and filters from air-monitoring
stations4. It has even been used to detect
endangered species that haven’t been spot-
ted for years, including a Brazilian frog
species (putatively assigned to Megaelosia
Korea, is testing an RNA editor to treat hepato-
cellular carcinoma, the most common type of
liver cancer. In September 2022, the company
started a clinical trial in South Korea, which it
intends to expand internationally.
Rznomics’s approach involves mRNA splic-
ing — but, unlike Ascidian’s method, it doesn’t
use the cell’s own splicing machinery. Instead,
the company co-opted a naturally occurring
ribozyme, an RNA molecule that can induce
splicing in target regions of mRNA. Research-
ers engineered the ribozymes to cut open
mRNAs in tumour cells and insert a lethal
cargo: an RNA sequence that is translated into a
protein that generates a toxin that induces cell
death. When surrounding cancer cells come
into contact with these cells, the toxin spreads,
promoting their death as well. The therapeu-
tic molecule replaces an RNA sequence that is
associated with tumour growth.
The use of the splicing approach against
more than one disease is very exciting, says
Lever, who is also the chief medical officer
of Spliceor in Cambridge, UK, a firm that
is working on RNA-splicing therapies. “It
opens up a whole new range of possibilities
of treatment for things which otherwise can’t
be treated.”
bocainensis) that researchers had thought
went extinct in the 1960s(ref. 5).
Kristy Deiner, an environmental scientist
at the Swiss Federal Institute of Technology
(ETH) in Zurich who is leading the massive
lake project, says that eDNA represents a
“paradigm shift” in how scientists monitor
biodiversity. Deiner’s research group has
already received applications from more than
500 people across 101 countries to participate
in collecting eDNA from their local lakes and
shipping the samples to ETH Zurich.
These global-scale projects are “really what
the eDNA community needs”, says Philip
Francis Thomsen, an environmental scientist
at Aarhus University in Denmark and a volun-
teer for the lake project.
“By involving citizens, we not only increase
the geographical scope of our sampling but also
foster a sense of public ownership and aware-
ness regarding global biodiversity issues,” says
Cátia Lúcio Pereira, the project’s coordinator,