Science - USA (2018-12-21)

SCIENCE sciencemag.org

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Short RNA molecules

attach to messenger

RNA (blue), preventing

translation into proteins.

A drug based on a gene-silencing mech-

anism called RNA interference (RNAi)

won regulatory approval this year. The

long-awaited step could be the harbinger

of a new class of drugs targeting disease-

causing genes.

Twenty years ago, two U.S. geneticists

discovered that short RNA molecules

can disrupt the translation of genes by

attaching to the messenger RNA that

carries a gene’s message to the cell’s

proteinmaking machinery. The advance

won them a Nobel Prize, but efforts to

turn it into medicine quickly hit hurdles.

Scientists struggled to keep the fragile

RNA molecules intact and direct them

to the right tissue. By 2008, research-

ers at Cambridge, Massachusetts–based

Alnylam Pharmaceuticals thought they

had a solution: a lipid nanoparticle that

would protect the gene-silencing RNA

and ferry it to the liver. There, they

hoped, it could treat a rare disease called

hereditary transthyretin amyloidosis by

blocking the production of a misfolded

protein that builds up and causes heart

and nerve damage.

“We set off with great haste and enthu-

siasm,” says Akshay Vaishnaw, Alnylam’s

president of R&D. But the new nano-

particle didn’t release enough RNA into

liver cells to knock down the problem

gene effectively in all patients. A more po-

tent formulation worked in human trials

and became the intravenous drug Onpat-

tro, which won clearance from U.S. and

EU regulators this year and hit the market

with a $ 450 , 000 - per-year list price.

The approval, along with the 2016 ap-

proval of a different class of RNA-based

drug, has invigorated the field, says

Frank Slack, a developmental biologist at

Beth Israel Deaconess Medical Center in

Boston who studies another type of

small RNA molecule. Many RNAi re-

searchers are now shifting their attention

to a newer delivery method: hooking

chemically stabilized RNA onto a sugar

molecule that homes in on the liver. Al-

nylam has developed a similar approach

to target tissues beyond the liver, such

as the eye and the central nervous system.

Getting RNA to accumulate in certain

tissues, including the heart, will be a

challenge, says Slack, but Alnylam’s suc-

cess “has just opened the flood gates.”

—Kelly Servick

2 PEOPLE’S CHOICE

Gene-silencing

drug approved

Published by AAAS

on December 24, 2018^

http://science.sciencemag.org/

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