Researchers target specific gene
mutation causing ALS, dementia
Johns Hopkins scientists have developed
new drugs that – at least in a laboratory dish
– appear to halt the brain-destroying impact
of a genetic mutation at work in some forms
of two incurable diseases, amyotrophic lateral
sclerosis (ALS) and dementia.
They made the finding by using neurons
they created from induced pluripotent
stem cells (iPS cells), which are derived
from the skin of people with ALS who
have a gene mutation that interferes with
the process of making proteins needed for
normal neuron function.
“Efforts to treat neurodegenerative diseases
have the highest failure rate for all
clinical trials,” says Jeffrey D. Rothstein,
M.D., Ph.D., a professor of neurology and
neuroscience at the Johns Hopkins University
School of Medicine and leader of
the research described online this week
in the journal Neuron.
“But with this iPS
technology, we think we can target an exact
subset of patients with a specific mutation
and succeed. It’s individualized brain
therapy, just the sort of thing that has been
done in cancer, but not yet in neurology.”
Scientists in 2011 discovered that more
than 40% of patients with an inherited
form of ALS and at least 10% of patients
with the non-inherited sporadic form have
a mutation in the C9ORF72 gene.
mutation also occurs very often in people
with frontotemporal dementia, the second-
most-common form of dementia after Alzheimer’s disease. The same research
appeared to explain why some people develop
both ALS and the dementia simultaneously
and that, in some families, one
sibling might develop ALS while another
might develop dementia.
In the C9ORF72 gene of a normal person,
there are up to 30 repeats of a series
of six DNA letters (GGGGCC); but in
people with the genetic glitch, the string
can be repeated thousands of times. Rothstein,
who is also director of the Johns
Hopkins Brain Science Institute and the
Robert Packard Center for ALS Research,
used his large bank of iPS cell lines from
ALS patients to identify several with the
C9ORF72 mutation, then experimented
with them to figure out the mechanism by
which the “repeats” were causing the brain
cell death characteristic of ALS.
In a series of experiments, Rothstein says,
they discovered that in iPS neurons with
the mutation, the process of using the DNA
blueprint to make RNA and then produce
protein is disrupted. Normally, RNA-binding
proteins facilitate the production of
RNA. Instead, in the iPS neurons with the
C9ORF72 mutation, the RNA made from
the repeating GGGGCC strings was bunching
up, gumming up the works by acting like
flypaper and grabbing hold of the extremely
important RNA binding proteins, including
one known as ADARB2, needed for the
proper production of many other cellular
RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts
of many other normal RNAs and made the
cells very sensitive to stress.
To counter this effect, the researchers
developed a number of chemical compounds
targeting the problem. This compound
behaved like a coating that matches
up to the GGGGCC repeats like velcro,
keeping the flypaper-like repeats from attracting
the bait, allowing the RNA-binding
protein to properly do its job.
Rothstein says Isis Pharmaceuticals
helped develop many of the studied compounds
and, by working closely with the
Johns Hopkins teams, could begin testing it
in human ALS patients with the C9ORF72
mutation in the next several years.
with the National Institutes of
Health, plans are already underway to begin
to identify a group of patients with the
C9ORF72 mutation for future research.
Gene variants associated with immune
system and autoimmune disease
Numerous studies have reported that
certain diseases are inherited. But genetics
also plays a role in immune response,
affecting our ability to stave off disease,
according to a team of international researchers.
The new findings, from the SardiNIA Study of Aging, supported in
part by the US National Institute on Aging
(NIA) at the National Institutes of
Health, are published in the September
26, 2013 issue of Cell. The SardiNIA researchers found 89 independent gene
on the genome associated with regulating production of
immune system cells.
Five of these sites for the gene variants
coincide with known genetic contributors to autoimmune diseases,
and extend previous knowledge to identify the particular
cell types that are affected by these genes.
“We know that certain diseases run in families. From this study,
we wanted to know the extent to which relative immune resistance
or susceptibility to disease is inherited in families,” said David Schlessinger,
Ph.D., chief of NIA’s Laboratory of Genetics.
mother is rarely sick, for example, does that mean you don’t have to
worry about the bug that’s going around? Is immunity in the genes?
According to our findings, the answer is yes, at least in part.”
The study team, led by Francesco Cucca, M.D., director of the
National Research Council’s Institute of Genetic and Biomedical
Research in Italy, discovered that variants in particular genes had
very significant effects on the levels of one or more particular types
of immune system cells.
A number of these genes are also implicated
in risk for various autoimmune diseases, including ulcerative
colitis, multiple sclerosis, rheumatoid arthritis, and celiac disease.
Understanding the genes affecting immune system cells and
risk for autoimmune disease is the first step in developing therapies
that are personalized according to an individual’s needs, although
more research is needed to further characterize the role
genetics plays in the complex dynamics of the immune system,
the researchers pointed out.
The human immune system is a complex network of cells, tissues,
and organs working together to fight disease and keep us
at optimal health and function.
Our first line of defence, the
innate immune system, includes barriers, like skin and mucus
as well as specific cells and molecules providing a prompt but
nonspecific response to harmful germs – pathogens – preventing
them from entering the body or eliminating them rapidly
after infection. The second line of defence, the adaptive immune
system, engages the body to produce, store, and transport
cells and molecules providing more specific responses to combat
The immune system has evolved to reject pathogens
and even some cancers, but high levels of immune function can
also make the body prone to autoimmune disease. Autoimmune
diseases occur when the body uses the immune system against
itself, attacking normal, healthy cells.
The number of adaptive immune system cells available to attack
a pathogen or, in the case of autoimmune disease, attack healthy
cells, is what appears to be regulated by genetics.
research team tested the heritability of this immune response using
a genome-wide association study, looking at approximately 8.2
million variants in blood samples taken from 1,629 Sardinians.
Small, single-letter variations in genes naturally occur
throughout the DNA code and are generally without effect
on any specific trait.
However, in some instances, scientists
find that a particular variant is more common among people
with a trait or disease. In the analyses, researchers identified 89 independent
and 53 sites associated with immune cell characteristics. Most of
these associations were previously undiscovered. Some had been
identified before in other studies, but without firm statistical significance.
The researchers compared their findings with data in public
repositories, and in some cases, found that these genes had already
been associated with autoimmune disease.
This finding is the most recent of several discoveries made by
the SardiNIA study itself and in conjunction with other groups in
international consortia. Previous findings identified gene associations
with height, fasting blood sugar, cholesterol and other fats
in the blood, beta-thalassemia (a blood disorder), and uric acid
levels, which can contribute to gout and risk of heart and kidney
One of the unique features of the investigation is its study population
– the Sardinians. “The lineage of most Sardinians goes back
approximately 20,000 years, to the Mediterranean island’s original
settler population – and an ideal group for this type of research,” said Cucca. “We have learned that in case after case, findings in Sardinia
have been applicable world-wide.”