10 Technology Quarterly |Personalised medicine The EconomistMarch 14th 2020
21cally underpowered. Giving Jessica a carefully tailored low-carbo-
hydrate diet activated an alternative way of getting calories to her-
brain. Another situation in which knowledge gives huge power is
Brown-Vialetto-Van Laere disease, a rare form of motor-neurone
disease that strikes in childhood. Faults in the genes SLC52A2and
SLC52A3reduce the body’s stocks of a protein that transports ribo-
flavin (vitamin B2) from the gut into the blood stream. High doses
of riboflavin can provide great benefits to many such patients—
but they will not get them if they do not know they need them.
Most of those with rare diseases cannot be provided with such a
positive outcome on the basis of knowledge alone. But a secure di-
agnosis still helps. For one thing, the diagnostic odyssey is ended:
no need for further invasive inquiry. And then there is support,
which matters a lot. Accurate diagnosis lets people find others in
similar straits to exchange advice, sympathy—and plans.
A genetic understanding of rare diseases also provides valuable
insights into common ones. If drug developers have a target with a
well defined causal role in some sort of disease, their studies are
twice as likely to lead to a working drug than if they do not. The
study of rare diseases provides insights of that sort which can be
used to develop treatments that are much more widely applicable.
That is why it continues to matter to more than just the families
suffering from them.Start making antisense
Studies of two rare genetic disorders in which bones grow too ea-
gerly, sclerosteosis and van Buchem’s disease, revealed that both
involved mutations in SOST, a gene that describes a protein now
called sclerostin. When expressed in bone-building cells, scleros-
tin turned out to suppress bone growth—hence the bone over-
growth problems when the gene is faulty. This opened up the pos-
sibility that patients without enough bone growth might benefit
from a drug that inhibited sclerostin. That has led to the develop-
ment of antibodies against sclerostin as a new strategy for treating
osteoporosis. Van Buchem’s disease is almost as rare as Jansen’s;
but in ageing populations osteoporosis is a public-health scourge.
Similarly, studies of a Chinese family with a rare form of eryth-
romelalgia, which causes burning pain and redness in the feet, are
driving the development of new painkillers. Studies of the faulty
PCSK9gene found in families with a genetic disorder that gives
them poor coronary health inspired a whole class of new anti-
cholesterol drugs that are more effective than statins.
A wrinkle on this approach is to find people with disease-caus-ing mutations who stay healthy, or whose disease progresses slow-
ly. These people contain genes that may protect them from harm,
which might be useful in creating new therapies for others. Maze
Therapeutics, based in San Francisco, is looking for “genetic modi-
fiers” that alter the course of conditions like als(also known as
Lou Gehrig’s disease). This disease is normally fatal within a cou-
ple of years. But in some sufferers, such as the late physicist Ste-
phen Hawking, it develops much more slowly.
Yet as humanity’s knowledge of disease mechanisms has
grown dramatically through the study of rare inherited diseases,
the development of treatments for those diseases themselves has
failed to keep pace. Conditions that blight lives by the dozen or
hundred are not big markets.
Many hope that various new technologies could drastically re-
duce the costs of bespoke treatments for at least some congenital
diseases. Most drugs today work by targeting a protein—either one
of the body’s proteins that is misbehaving, or a protein in a patho-
gen that is achieving its goals all too well. The drug has to be tai-
lored to the shape and activity of the protein it targets, while not
messing up the workings of other inoffensive proteins that are do-
ing vital work. That isn’t easy.
What, though, if you could stop a problematic protein from be-
ing made in the first place? For a cell to make a protein, it first
needs to make a copy of the gene sequence that describes that pro-
tein. This copy is called a messenger rna, or mrna. If you know
the sequence of the gene, it is easy to work out the sequence of its
mrna, and from that design a short strand of dnathat, by dint of
its own sequence, will stick to that mrna, thus rendering it useless
(see diagram).
Such dna-based saboteurs are called “antisense oligonucleo-
tides” (asos). They are now being used to treat various faulty-gene
diseases, including a particular form of spinal muscular atrophy
(sma), some types of Duchenne muscular dystrophy and familial
hypercholesterolemia—the disease that led to the design of new
anti-cholesterol drugs. There are trials under way to see if an aso
can slow the progression of Huntington’s disease, a lethal degen-Attacking the messenger
Howtointerceptanddestroya faultygeneticmessage→→Source: The Economist→Person treated with antisense drugPerson with a disease
Genetic instructions
which contain a
mutation......are transmitted to protein-
making mechanisms by a
messenger RNAAntisense drugs bind
to messenger RNA,
making it uselessThis information
is used to create a
protein with a fault