Genetic forms of frontotemporal dementia and
amyotrophic lateral sclerosis
Frontotemporal dementia (FTD) is a common dementia
in people aged under 65 years [1,2] characterized by
impaired social comportment, apathy, lack of empathy,
cognitive decline, and appetite changes with neuro patho-
logic and genetic features overlapping with amyotrophic
lateral sclerosis (ALS) in a subset of patients. ALS is a
neurodegenerative disorder that, in its most common
form, causes both upper and lower motor neuron signs
with muscle wasting and a rapid progression to death
within 3 to 5 years. Th ese two diseases often coexist, with
22% of ALS patients meeting FTD diagnostic criteria and
a greater number (48%) manifesting cognitive or
behavioral abnormalities of FTD but not the full
syndrome [3,4]. Conversely, 15% of FTD patients display
signs of motor neuron disease or ALS , suggesting that
these diseases lay along the same disease spectrum. A
family history of dementia is present in about 40% of
FTD cases, with an autosomal dominant pattern of
inheri tance identifi able in 10% of cases . ALS has an
autosomal dominant pattern in up to 10% of cases as well
. Previously, most of the known genetic causes of FTD
were attributed to mutations on chromosome 17, in
genes encoding the microtubule associated-protein tau
(MAPT)  or progranulin (GRN) [9,10]. Prior to the
discovery of C9ORF72, the most common mutation
associated with ALS disease was in superoxide dismutase
(SOD1) [11,12]. Other mutations identifi ed in familial
ALS include UBQLN2 , TDP43, FUS, OPTN, and
The discovery of C9ORF72
A variety of prior linkage analysis studies of families in
which members have developed FTD, ALS or both (FTD-
ALS) in an autosomal dominant inheritance pattern
suggested linkage to a region on chromosome 9p [14-22].
A collaborative eff ort between our group at the University
of California, San Francisco (UCSF), researchers at the
Mayo Clinic, and the University of British Columbia
(UBC) led to the discovery in 2011 that a hexanucleotide
repeat expansion in a non-coding region, the promoter or
the fi rst intron, of the chromosome 9 open reading frame
72 (C9ORF72) gene was the cause of FTD and ALS in the
most strongly linked family (Vancouver San Francisco
Mayo-20 (VSM-20) family) to chromosome 9p. Analysis
of other autosomal dominant FTD kindreds revealed this
mutation to be the most common genetic cause of FTD
(12% of familial FTD; 3% of sporadic FTD), ALS (23% of
familial ALS; 4% of sporadic ALS) or combined FTD-ALS
at each of these institutions [12,16,23]. At the same time,
another group found the same genetic mutation in a
Finnish population with higher prevalence (46% of
Frontotemporal dementia (FTD) is a common dementia
syndrome in patients under the age of 65 years
with many features overlapping with amyotrophic
lateral sclerosis (ALS). The link between FTD and
ALS has been strengthened by the discovery that a
hexanucleotide repeat expansion in a non-coding
region of the C9ORF72 gene causes both familial and
sporadic types of these two diseases. As we begin to
understand the pathophysiological mechanisms by
which this mutation leads to FTD and ALS (c9FTD/
ALS), new targets for disease-modifying therapies
will likely be unveiled. Putative C9ORF72 expansion
pathogenic mechanisms include loss of C9ORF72
protein function, sequestration of nucleic acid binding
proteins due to expanded hexanucleotide repeats,
or a combination of the two. New animal models
and other research tools informed by work in other
repeat expansion neurodegenerative diseases such
as the spinocerebellar ataxias will help to elucidate
the mechanisms of C9ORF72-mediated disease.
Similarly, re-examining previous studies of drugs
developed to treat ALS in light of this new mutation
may identify novel FTD treatments. Ultimately, research
consortiums incorporating animal models and well-
characterized clinical populations will be necessary
to fully understand the natural history of the c9FTD/
ALS clinical phenotypes and identify biomarkers and
therapeutic agents that can cure the most common
form of genetically determined FTD and ALS.
© 2010 BioMed Central Ltd
Treatment implications of C9ORF72
Sharon J Sha* and Adam Boxer
University of California, San Francisco, Memory and Aging Center, Box 1207,
San Francisco, CA 94143-1207, USA
Sha and Boxer Alzheimer’s Research & Therapy 2012, 4:46
© 2012 BioMed Central Ltd
familial ALS; 21% of sporadic ALS) . In the initial
studies, the clinical disease phenotypes associated with
this mutation most commonly included FTD, ALS, and
FTD-ALS [25-27]. Less frequently, other phenotypes,
such as the non-fl uent variant of primary progressive
aphasia (nfvPPA) and semantic variant of primary pro-
gres sive aphasia (svPPA), both with and without motor
neuron disease, have been observed [12,28,29] in addition
to Alzheimer’s disease . At autopsy, examination of
these mutation carriers identifi ed frontotemporal lobar
degeneration-TAR DNA binding protein-43 (TDP-43;
FTLD-TDP) neuropathology in all. Th e location, mor-
pho logy, and distribution of TDP-43 immunoreactive
inclusions defi ne the TDP subtype of FTD pathology 
and two subtypes, FTLD-TDP type A and type B, have
been reported in association with the C9ORF72 mutation
[26-32]. Additionally, immunoreactivity to ubiquilin
(UBQLN) and p62 (sequestosome 1), proteins involved in
cellular protein degradation pathways, as well as an as yet
unidentifi ed protein, have been noted in mutation
carriers [12,16,26-29,32-35] and have been hypothesized
to be signature pathological features of C9ORF72-related
Th e discovery of the C9ORF72 mutation has important
treatment implications for patients with FTD.
First, this mutation may reveal important mechanistic
information about the molecular triggers for FTD and
ALS, thus allowing the identifi cation of novel drug
targets. In addition, the discovery of C9ORF72 mutations
as a cause of FTD may help to resolve some confusing
dissociations between two genes that, when mutated,
cause ALS but rarely FTD, yet are found at autopsy in the
form of insoluble protein deposits in both disorders:
TDP-43 and fused in sarcoma (FUS). Since both TDP-43
and FUS are RNA binding proteins, the fi nding that
C9ORF72 expansions have the potential to alter RNA
binding protein levels may be particularly important for
understanding the biochemical mechanisms underlying
FTD-ALS. Specifi cally, C9ORF72 repeat expansions
decrease the levels of TDP-43 or FUS, which could aff ect
RNA transport or processing and may be a key patho-
physiological trigger for FTD-ALS. In addition, C9ORF72
mutations could also impair RNA metabolism if the
hexanucleotide repeat expansions sequester other nucleic
acid binding proteins . Th us, cellular RNA processing
and transport mechanisms are likely to be key drug
targets for FTD-ALS.
Second, since the C9ORF72 mutation is by far the most
prevalent cause of FTD and ALS, accounting for 11.7% of
familial FTD, 22.5% of familial ALS, and 4% of sporadic
ALS , and as much as 46% of familial ALS and 21.1%
of sporadic ALS in a Finnish population , a treatment
developed for C9ORF72 mutation carriers might even-
tually fi nd a use in both inherited and sporadic forms of
these diseases, potentially benefi tting a signifi cant pro-
portion of patients with both disorders. Both possibilities
are discussed in greater detail below.
Drug discovery opportunities aff orded by the
Target identifi cation
Targeting the pathological mechanism responsible for
C9ORF72-associated FTD and ALS is a logical fi rst step
in leveraging this discovery to develop new treatments
for both C9ORF72-associated disease as well as other
forms of FTD and ALS. Two non-mutually exclusive
mecha nisms might explain the pathogenesis of C9ORF72-
related FTD-ALS. Expanded repeat disorders in untrans-
lated regions or introns generally can cause disease
pathogenesis by loss of function due to decreased protein
expression, or by toxic gain of function due to inclusion
of multiple repeats within DNA or RNA transcripts .
Th e hexanucleotide expansion can occur in the C9ORF72
gene promoter region that binds to transcription regu-
latory factors. Th is can lead to decreased C9ORF72 gene
transcription and ultimately protein expression. Consis-
tent with this hypothesis, one of the three RNA splice
variant mRNAs from C9ORF72 was decreased in muta-
tion carriers compared to non-carriers in two separate
studies [23,37]. Th us, one target for new FTD drugs
might be agents that increase C9ORF72 protein levels, or
make up for the loss of C9ORF72 protein function.
Expanded hexanucleotide repeats in RNA transcripts
could result in aberrant splicing or generation of RNA
fragments that form nuclear inclusions. Th ese foci could
sequester RNA-binding proteins in the nucleus and alter
regulation and splicing of other genes. As a result, the
C9ORF72 hexanucleotide expansion RNA foci could
have multi-systemic eff ects. Such a sequestration mecha-
nism occurs in other non-coding repeat expansion
diseases such as myotonic dystrophy (DM1) and fragile
X-associated tremor/ataxia syndrome (FXTAS) [38,39],
which have both neuronal and non-neuronal phenotypes.
Th is suggests that a second target for new FTD therapies
would be the repeat expansions themselves or the RNA
fragment foci that form as a result of the repeat expan-
sions. A fi nal possibility is that RNA-binding protein
sequestration by expanded hexanucleotide repeats and
haploinsuffi ciency of C9ORF72 protein both contribute
to the disease mechanism and could be targets for thera-
peutic intervention (Figure 1).
RNA as a therapeutic target
Clues to identifying which compounds might prove
effi cacious for C9ORF72-related disease can be found by
looking at other neurodegenerative disease models with
Sha and Boxer Alzheimer’s Research & Therapy 2012, 4:46
Page 2 of 7
similar repeat expansion pathophysiology. DM1, FXTAS,
and several spinocerebellar ataxias have repeat expan-
sions in non-coding regions that may lead to targeted
drug discovery eff orts or already have these underway
. Examining previously tested drugs (both failed and
promising) and drug targets in these disorders might
provide starting points for C9ORF72. RNA antisense
oligonucleotides have been studied in DM1 [41,42], were
tolerated in a phase I clinical trial for SOD1-related ALS,
and could be applied in c9FTD/ALS. Th ese oligonucleo-
tides could act to interrupt sequestration of critical
proteins by toxic RNA hexanucleotide repeat expansions
or potentially alter the transcription or splicing of
C9ORF72. Alternatively, the oligonucleotides could
disrupt RNA hairpin structures or other steric confor ma-
tions that are thought to have toxic eff ects in other repeat
expansion mutation diseases [36,39,43].
TDP-43 as a drug target
TDP-43 is another attractive drug target in C9ORF72-
related FTD/ALS. Although TDP type A and B have been
reported, all autopsy studies of C9ORF72 mutation
carriers thus far have been noted to have TDP-43
pathology. Even with the variable FTLD-TDP pathology,
a compound that increases clearance or inhibits aggrega-
tion of TDP-43 protein could be useful in c9FTD/ALS.
One compound that does this is methylene blue, which
can decrease TDP-43 aggregation in vitro , although,
thus far, methylene blue has failed to demonstrate
improve ments in motor function in TDP-43 mouse
models of ALS . Methylene blue may also promote
autophagy . Compounds that increase cellular protein
turnover via autophagy or the proteasome pathway might
also be candidate therapies for C9ORF72-related disease,
particularly since there is evidence of accumulation of
proteins such as UBQLN and p62 in these cases .
Finally, if developed, immunotherapies (vaccines or
neutralizing antibodies) targeted towards TDP-43 would
be attractive therapies. A variety of such therapies are in
development for neurodegenerative diseases with tau,
amyloid, and synuclein pathology.
In order to determine which mechanism(s) is/are patho-
genic, cell-based studies or animal models of C9ORF72-
related disease are needed. Transgenic mouse models
have been used to study many degenerative diseases,
including Alzheimer’s disease and ALS, and may ulti-
mately be most useful for developing C9ORF72-targeted
therapeutics. In addition, if C9ORF72 homologues exist
in Caenorhabditis elegans and Drosophila, these model
systems may also be useful for target identifi cation .
Induced pluripotent stem cells have also been used to
create both patient- and disease-specifi c cells  in
order to better study the pathophysiology . High
throughput drug screening using cells from C9ORF72
mutation gene carriers, such as those that we have
derived from the VSM-20 family, could be used to screen
for potential compounds. When therapeutic interven-
tions are identifi ed, patient-specifi c cell lines can be used
to test the toxicology and potential benefi t for that
individual patient. Given the heterogeneity of C9ORF72
phenotypes, with both slowly and rapidly progressive
forms of disease , use of patient-specifi c induced
pluripotent stem cells may be particularly useful for
Application of current ALS experimental therapeutics to
Other potential agents to consider for treatment of
c9FTD/ALS are ones already used or in late stage clinical
trials in ALS . Considering the pathological, genetic,
and phenotypic similarities now known to be shared with
FTD, drugs found to be effi cacious for ALS might also be
expected to benefi t individuals with FTD due to TDP-43,
particularly those caused by C9ORF72. Riluzole, a neuro-
protective agent thought to block voltage-dependent
sodium channels on glutamatergic nerve terminals, is the
Figure 1. Drug development opportunities resulting from the C9ORF72 mutation discovery. The fi gure shows a general, hypothetical drug
development plan with opportunities resulting from the discovery at multiple pre-clinical and clinical development stages. ALS, amyotrophic lateral
sclerosis; C9ORF72, chromosome 9 open reading frame 72; FTLD, frontotemporal lobar degeneration; TDP, TAR DNA binding protein.
? C9ORF72 protein
? Abolish RNA
? Increase RNA
? Identify other
genes or genes or
? Phase 2 trial
? Biomarker(s) of
2 t i l
? Phase 3 trial
? Inclusion based on
? Possibility of
prevention trial in
3 t i l
? Expansion binding
? Drugs repurposed
from ALS trials
? IPS cells derived
? Orphan status
? Possible extended
Sha and Boxer Alzheimer’s Research & Therapy 2012, 4:46
Page 3 of 7
only US Food and Drug Administration-approved drug
to treat ALS and has been shown to reduce mortality,
though modestly [52-54], and may be worthwhile testing
in preclinical C9ORF72 models. Dexpramipexole, an
enantiomer of pramipexole, is thought to have anti-
infl ammatory properties and was recently found to
attenuate the decline in function using the ALS
Functional Rating Scale-Revised (ALSFRS) in a dose-
dependent manner with good tolerability in ALS .
Fingolimod, an anti-infl ammatory drug used to treat
multiple sclerosis in several countries outside the United
States, will soon begin phase II clinical trial in ALS 
and may also have promise in FTD. Clinical trials of
agents that have clearly shown no benefi t in ALS, like
those with lithium , may also be useful in guiding
such therapies away from use in FTD due to C9ORF72.
To streamline identifi cation of promising treatments
for C9ORF72-related disease, cases from previous ALS
clinical trials should be genotyped. Given the high
prevalence of the C9ORF72 mutation in ALS, agents that
are benefi cial for sporadic ALS may also be useful in
C9ORF72-associated FTD and FTD-ALS. Such a
response might be predicted if post hoc genetic analyses
of previous ALS clinical studies showed that C9ORF72
patients clearly benefi ted from a drug. Even if an overall
ALS clinical trial was negative, it remains possible that
C9ORF72 carriers could have been a responsive sub-
popu lation in whom eff ects were masked by non-carriers.
Similarly, it would be of interest to genotype patients who
respond particularly well to a given therapy to assess
whether this relates to C9ORF72 gene status.
Identifying disease modifying factors
Studying patients who are carriers of the C9ORF72
mutation with particular attention to the genetic and
environmental factors that can slow or alter the disease
phenotype is another way to learn about the disease
mechanism to identify potential drug targets. An example
of a slowly progressive FTD (FTD-SP) phenotype of
C9ORF72 disease has been described recently . FTD-
SP patients have features of FTD, yet have been noted to
have minimal atrophy on structural MRI and little to no
progression on sequential neuropsychological measures.
Identifying the factors that aff ect the rate of disease
progression like those in FTD-SP patients would provide
insight into other targets for potential therapies. An
important question that has yet to be answered is
whether the number of hexanucleotide repeats aff ects the
C9ORF72 phenotype, similar to other repeat expansion
disorders. Preliminary studies have found that normal
controls have no more than 23 to 30 repeats of the
hexanucleotide (GGGGCC), but carriers of the mutated
alleles usually have over 60  and as high as 1,600 ,
although the number of repeats is not easily quantifi ed.
It is also likely that other genes exist that modify the
C9ORF72 phenotype. For example, in FTLD-TDP caused
by progranulin (GRN) mutations, a number of genes and
microRNAs have been identifi ed that alter the disease
phenotype . Th e presence of certain TMEM106B
single nucleotide polymorphisms was shown to reduce
GRN mutation penetrance possibly by modifying pro-
granulin protein levels . TMEM106B could thus be a
target for new therapies for patients with GRN mutations,
and similarly, genes that modify C9ORF72 protein levels
or function would be good targets for drugs in C9ORF72
Studies such as COHORT-HD (Cooperative Hunting-
ton’s Observational Research Trial) that seek to identify
genetic and environmental factors that modify disease
progression are being pursued in other repeat expansion
diseases such as Huntington’s disease  and suggest
that similar eff orts should be pursued in c9FTD/ALS. A
large study like this, if employed for C9ORF72, could
identify both genetic and epigenetic factors that infl uence
the C9ORF72 hexanucleotide expansion phenotype.
Potentially, factors such as the number of hexanucleotide
repeats, brain atrophy pattern at baseline, or environ-
mental exposures could be used to identify other targets
for C9ORF72 disease modifying agents.
Human clinical trials
In preparing for clinical trials on mutation carriers of
C9ORF72, a fi rst step would be to use the C9ORF72
geno type as a biomarker for diagnostic inclusion. If the
rate of progression of disease is related to the length of
repeats, as seen in other repeat expansion diseases like
spinocerebellar ataxias and Huntington’s disease, this
could also help to select certain populations of C9ORF72
mutation carriers who are expected to progress at the
same rate. To determine if a particular agent is modifying
the course of C9ORF72 disease or delaying expression of
the disease phenotype in a mutation carrier, a biomarker
that accurately captures disease progression would be
A cure for C9ORF72-related disease is more likely if a
disease modifying treatment can be initiated early in the
course of the disease, ideally before the onset of disease.
By following the model of other groups that study
autosomal dominant forms of dementia, such as the
Dominantly Inherited Alzheimer Network (DIAN), future
researchers can emulate methods to study the eff ect of
the C9ORF72 mutation in presymptomatic mutation
carriers. DIAN is a clinical research network that studies
the presymptomatic events that occur in autosomal
dominant Alzheimer’s disease gene (mainly presenilin 1
and amyloid precursor protein) carriers to learn about
the disease. DIAN has identifi ed changes in neuroimaging
and fl uid biomarkers that precede the development of
Sha and Boxer Alzheimer’s Research & Therapy 2012, 4:46
Page 4 of 7
AD in these cases, often by 15 years or more. Biomarkers
will be crucial to gauge the effi cacy of therapeutic agents
in clinical trials of disease modifying agents initiated
before the patient displays clinically manifest disease.
Such a presymptomatic ‘prevention’ trial is currently
planned for DIAN as well as another similar Alzheimer’s
disease initiative called the Alzheimer’s Disease Preven-
tion Initiative. Once biomarkers that capture C9ORF72
disease progression are developed (one possibility might
be cerebrospinal fl uid TDP-43 measurements), similar
C9ORF72 prevention clinical trials might be considered.
Th e discovery of the hexanucleotide repeat expansion in
the C9ORF72 gene is a major step forward in under-
standing the pathophysiology of the FTD/ALS spectrum
of diseases. With this information, the time is ripe for
developing treatments that target specifi c C9ORF72-
asso ciated disease mechanisms. Moreover, the link
between various inherited neurodegenerative diseases
like FXTAS, DM1, spinocerebellar ataxias, and FTD is
becoming stronger as more is learned about the patho-
genic mechanisms of nucleotide expansion repeat diseases.
A possible common mechanism for all FTLD-TDP
diseases involving RNA processing abnormalities could
also facilitate the identifi cation of novel therapeutic
agents. In order to achieve the goals of fi nding a disease-
modifying agent for C9ORF72 FTD/ALS, an appropriate
biomarker of disease progression or severity must be
identifi ed to be used in human pharmacodynamics and
effi cacy studies. For example, if TDP-43 is the drug
target, then fi nding an in vivo tool for measuring the
burden of pathology, such as a cerebrospinal fl uid or
imaging biomarker, might be necessary. Likewise, if
raising disease-relevant mRNA levels is the goal of a
potential compound, it is important to demonstrate that
the RNA levels change with disease. Measuring cerebro-
spinal or plasma RNA levels might be one way to demon-
strate such target engagement in human subjects. Future
clinical trials could also use measurements of such levels
as a surrogate endpoint of effi cacy. Further research is
required before specifi c C9ORF72-related compounds
can be developed and tested in humans, but the discovery
of the C9ORF72 mutation suggests that an important
pathophysiological mechanism involves FTLD-TDP RNA
processing. Th is fi nding may lead to new therapies for
FTD, ALS, and possibly other repeat expansion degenera-
ALS, amyotrophic lateral sclerosis; C9ORF72, chromosome 9 open reading frame 72;
DIAN, Dominantly Inherited Alzheimer Network; DM1, myotonic dystrophy; FTD,
frontotemporal dementia; FTD-SP, slowly progressive FTD; FTLD, frontotemporal
lobar degeneration; FXTAS, fragile X-associated tremor/ataxia syndrome; GRN,
progranulin; MRI, magnetic resonance imaging; TDP, TAR DNA binding protein;
UBQLN, ubiquilin; VSM-20, Vancouver San Francisco Mayo-20 family.
SJS declares no competing interests. AB has been a consultant for Bristol
Myers Squibb, Genentech, Plexikkon, Phloronol, Envivo and TauRx and receives
research support from Allon Therapeutics, Bristol Myers Squibb, Janssen,
Forest, Pfi zer and Genentech.
AB is funded by NIH grants R01AG038791, R01AG031278, the John Douglas
French Foundation, Alzheimer’s Drug Discovery Foundation, the Association
for Frontotemporal Degeneration, the Silicon Valley Foundation, the Agouron
Institute, the Tau Research Consortium and the Hellman Family Foundation.
Published: 27 November 2012
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Cite this article as: Sha SJ, Boxer A: Treatment implications of C9ORF72.
Alzheimer’s Research & Therapy 2012, 4:46.
Sha and Boxer Alzheimer’s Research & Therapy 2012, 4:46
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