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MESSENGER RNA THERAPIES ARE FINALLY FULFILLING THEIR PROMISE  
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Drew Weissman
March 1, 2022
Scientific American
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_ Instructing our cells to make specific proteins could control
influenza, autoimmune diseases, even cancer _

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_Editor’s Note (10/2/23): Katalin Karikó and Drew Weissman were
awarded the __2023 Nobel Prize in Physiology or Medicine for their
work on mRNA_
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which led to COVID vaccines that have protected billions of people.
Weissman describes the promise of mRNA therapies in this 2022
feature._

In just 17 years, messenger RNA therapies went from proof of concept
to global salvation. The Pfizer-BioNTech and Moderna vaccines for
COVID-19 have been given to hundreds of millions of people, saving
countless lives.

In 2005 Katalin Karikó and I created a way to make mRNA molecules
that would not cause dangerous inflammation when injected into an
animal's tissue. In 2017 Norbert Pardi and I demonstrated that
modified mRNA, carried into human cells by a fatlike nanoparticle, was
protected from being broken down by the body and prompted immune cells
to generate antibodies that neutralize an invading virus more
effectively than the immune system could on its own. The COVID
vaccines made by Pfizer-BioNTech and Moderna both use this
mRNA-liquid-nanoparticle “platform”—known as mRNA-LNP. In large
clinical trials, it prevented more than 90 percent of the people who
received the vaccines from becoming ill.

These extremely promising trials, and massive studies of people who
have since received the vaccines, have finally given us sufficient
information about the safety and efficacy of mRNA vaccines in humans.
The platform outperformed more conventional approaches, in which
vaccines are grown in laboratory cell cultures or chicken eggs. The
rapid development also accelerated investment in further research. And
because the U.S. Food and Drug Administration and similar regulatory
agencies are now familiar with the technology, assessment of new
therapeutics should come readily.

Messenger RNA vaccines instruct cells to create proteins that induce
an immune response to an invader such as the SARS-CoV-2 virus,
training the immune system to attack the actual pathogen if it infects
the person in the future. These vaccines are easier to produce in
large quantities than conventional protein therapies (genetically
engineered versions of natural human or pathogen proteins) and
monoclonal antibody therapies (lab-produced molecules that attack
viruses in the same way that human antibodies do). And once a reliable
manufacturing facility is built, it can quickly switch to a new mRNA
vaccine or drug—unlike protein or monoclonal facilities, which must
reengineer production from the ground up for each new therapy.

Success has inspired researchers, companies and government labs to
pursue mRNA therapies for many infectious diseases, including
influenza, cytomegalovirus, herpes simplex virus 2, norovirus, rabies,
malaria, tuberculosis, dengue, Zika, HIV, hepatitis C and the entire
family of coronaviruses. In each case, researchers wanted to determine
exactly how mRNA-LNP vaccines induce potent antibody responses.

Work on mRNA vaccines also has expanded to certain cancers, food and
environmental allergies, and autoimmune diseases. Positive results
against ATTR amyloidosis, a fatal condition that involves the liver,
have already been produced in a phase 1 clinical trial. Although the
use of protein-based medications for certain illnesses is expanding
quickly, large doses are typically required, and production is often
difficult and expensive; mRNA delivery of therapeutic proteins could
help. The approach has already worked in animals for issues as
disparate as bone repair and asthma, and some treatments have advanced
to human clinical trials. The Defense Advanced Research Projects
Agency has even experimented with mRNA delivery of monoclonal
antibodies that could be tailored for previously unidentified
infectious diseases, with the goal of supplying reliable manufacturing
of such remedies within 60 days.

The concentrated COVID work has also helped make mRNA a leader in
nucleic acid therapeutics—approaches that can produce nearly any
protein made by a specific cell. The technique is starting to be
applied, and it could fight diseases in more convenient, less invasive
and less expensive ways. For example, the fda has approved gene
therapy for sickle cell anemia, and it is working in the U.S.,
although it requires marrow to be extracted from a person's bone,
treated and reinserted; mRNA therapy could be delivered to marrow with
a straightforward injection into a person's arm. If that works, sickle
cell treatment could be greatly expanded in countries where the
condition is widespread.

In a similar fashion, mRNA therapeutics could revolutionize the
treatment of many infectious diseases in developing countries, greatly
improving health-care equity. I have collaborated with labs around the
world. Thai investigators at the vaccine center at Chulalongkorn in
Bangkok and I made a Thai COVID vaccine and established a quality
manufacturing center to produce it for Thailand and seven surrounding
low- and middle-income countries. I undertook similar work in Africa
and eastern Europe, with plans to extend it to South America.

Plenty of hurdles remain, including the creation of a better supply
chain for delivering raw mRNA vaccine and materials needed for its
production worldwide, as well as improvements that could reduce the
dosage a person needs to receive. Yet the ease of mRNA production
should enable most countries to make their own medications, as long as
they can attract and retain researchers who can develop subsequent
therapeutics that in turn keep domestic, high-quality manufacturing
sites operating.

_DREW WEISSMAN
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professor of vaccine research at the University of Pennsylvania. The
nucleoside-modified mRNA-lipid-nanoparticle vaccine platform his
laboratory created is used in COVID-19 vaccines made by
Pfizer-BioNTech and Moderna. Weissman receives royalties from a patent
for nucleoside-modified mRNA that is licensed by those two companies._

This article was originally published with the title “Messenger RNA
Therapies Finally Arrived” in _Scientific American Special
Editions_ Vol. 31 No. 2s (April 2022), p. 54

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