the challenge for us is: there’s all these
possibilities—how do we focus in on the
things that we think will give us the high-
est probability of success and also prove
the technology before we expand it out
into many different indications?”
Much to prove
It remains to be seen whether the tech can
make good on its potential. Levanon says he
expects that, among successes, “there will be
many disappointments” in the coming years,
especially when it comes to designing effi-
cient guide RNAs. He notes that the bases
near the target site on an mRNA, as well as
the structure of the guide RNA itself, can
tweak the efficiency of ADAR activity, and
says that researchers will need to under-
stand more about why natural ADARs edit
when and where they do before they can
truly manipulate them with precision.
There’s also the obvious limitation
that ADARs only edit As into Is. That’s
one of twelve possible manipulations one
might want to make, notes Levanon; if
another base is desired in a given spot,
ADARs can’t help. There are enzymes that
edit cytosines (Cs) into uracils (Us)—the
RNA version of thymine (T)—and these
are now being explored, but that technol-
ogy is years behind, and as of yet, enzymes
that make other conversions either aren’t
known or aren’t well characterized. While
turning an A into an I (read as a G) may
be helpful in many cases—in more than
half of Rett Syndrome cases, for instance,
Mandel estimates—that’s not going to be
the case for every genetic disease.
With research at such an early stage,
the challenge of drug delivery still looms.
“It’s that next step of: Can I deliver the
payload to the target tissue? Can I deliver
it at a high enough concentration? And
can I deliver it so that you have a sus-
tained expression?” that may slow prog-
ress toward the clinic, says Huss.At least in terms of regulatory hur-
dles on the road to market, “a lot of
that ground has already been plowed”
by other RNA-based technologies,
Nakae says. “I think it’ll actually be an
easier path [to approval] than what
some of those other modalities faced.
But that said, they’ll still have to have
the preclinical data that shows that it’s
safe before it’s allowed to go forward.”
Among companies working on the tech-
nology, Nakae says, there are no obvious
frontrunners yet.
Nevertheless, “now that biotech com-
panies are involved... I’m hopeful that
things are going to accelerate with RNA
editing quickly,” says Mandel. And she
has reason to hope; in May 2021, the
Rett Syndrome Research Trust’s press
office wrote that RNA editing therapeu-
tics funded by the trust are expected to hit
clinical trials by the end of 2024. “It’s cer-
tainly an exciting time,” she says. JRead The Scientist
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