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2010 Research Grants
The following reports provide information about the
projects funded by the MND Research Institute of Australia in 2010.
Grants-in-aid
Dr
Julie Atkin
La Trobe
University, Melbourne.
Is Protein Disulphide Isomerase (PDI) a novel biomarker for
motor neuron disease?
Neurodegenerative
disorders (Alzheimer’s, Parkinson’s and Motor Neuron Diseases) share
common features: abnormal protein clumps within affected cells which are
linked to pathology. The lack of effective therapies coupled with the
aging population and the incipient projected dramatic increase in the
number of persons with neurodegenerative disorders in the coming
decades, highlights the need to urgently find effective treatment
strategies. Numerous potential therapeutic and/or preventive agents
have been tested in clinical trials to these conditions, yet most have
failed to show a clear therapeutic benefit. An important aid in drug
development and diagnosis is an accurate biomarker of disease severity
and progression. A molecule, called PDI, has the potential to meet both
these need.
We have evidence that
PDI prevents abnormal clumping in MND and hence has two novel potential
applications in these disease; (1) as a biological marker to tract
disease progression, (2) as a new treatment to improve disease
outcomes. We assess the first possibility in this proposal. The
evidence we obtained in our studies has led us to believe that PDI may
be a new and effective biomarker of MND.
We also tested PDI in
human cerebrospinal fluids from MND patients and unaffected individuals,
to determine whether PDI could be used to reliably measure disease
outcome and progression. We also hope that PDI could be used to predict
disease in patients with inherited forms of MND. If PDI can reliably
diagnose MND, this would facilitate future studies to establish a
diagnostic kit for MND or to design clinical trials of new drugs.
Peter Stearne Grant for Familial MND Research
Dr
Ian Blair
ANZAC Research Institute, NSW
Characterisation and investigation of a new transgenic mouse model
expressing mutant TDP-43.
The only proven causes
of MND are mutations in genes that lead to death of motor neurons. Using
these mutations, mice have previously been developed that mimic features
of MND. These animals, called mouse models of MND, have been a principal
tool for testing proposed disease treatments.
Unfortunately the
promise of treatments shown in existing mouse models have largely proven
unsuccessful in human trials. We recently described mutations in a new
MND gene, TDP-43. We have developed new mice that carry one of these
TDP-43 mutations. These mice are currently being bred in our laboratory
to establish this mouse colony and switch-on the defective gene. As a
disease with late age of onset, we are now monitoring and testing these
mice to establish whether they develop similar symptoms to MND. If so,
this new mouse model will be available for investigating the biology of
the disease and for evaluating treatments.
Mick Rodger MND Research Grant
A/Prof
Meng Inn Chuah
University of Tasmania.
Effect
of metallothionein and exercise on progression of MND.
The degeneration of
motor neurones in the spinal cord and brain of patients suffering MND is
the primary feature of this debilitating and ultimately fatal disease.
Unfortunately there are no clinical treatments that can stop or reverse
the progressive course of this disease. Metallothionein (MT) proteins
are known to be neuroprotective in several experimental models of
neuronal injury and disease. The aim of this project was to investigate
whether combining MT with an exercise regimen can result in improvement
in the functional and survival outcome of a mouse model of MND.
We are able to show that
MT injected into muscle can be detected rapidly in the blood system and
some of it appears to be excreted into the urine. We have also
developed a method to measure the amount of MT in the spinal cord.
Groups of mice have been undertaking exercise and/or MT injection. We
have recorded and continue to monitor their weights (twice a week), how
well they walk based on their footprints, and their grip strength. On
completion of the exercise treatment and when the mice reach their
end-point, their spinal cords and muscle tissue are isolated to
determine how much MT they contain. We are in the process of graphing
and analysing the progress of the mice. So far there do not appear to
be significant differences in the functional ability of the different
groups although at a few time points, mice which were exercising
appeared to have a more normal stride length and possibly a stronger
grip. We found large variability in the behavioural characteristics of
the mice so it is important that we base our analyses on a sufficiently
large sample before drawing firm conclusions. We hope to complete
functional analyses of the surviving mice, as well as analyses of MT in
the spinal cords in the next few months.
Our work is a first step
in determining whether MT in combination with exercise can be of benefit
to MND patients. It is likely that before any positive effects of MT
and/or exercise can be fully realised, additional experiments will be
required. These could include establishing the optimum dosage and
length of treatment. Funds permitting, we would also like to understand
how motor neurons in the MND spinal cord respond to MT.
Dr Peter
Crouch
Department of Pathology,
University of Melbourne.
Investigating cellular hypoxia as a causative factor in MND and as a
potential therapeutic target.
The fundamental
biological causes of decreased motor neurone function in MND remain
unknown. Some clues are evident in genetic forms of the disease, but
these forms of MND only account for a small minority of all cases.
Identifying the causes of decreased motor neurone function is an
essential step in developing new and more effective therapeutics to
treat MND.
Our research focuses on
demonstrating the mechanism of action for a novel therapeutic compound,
CuII(atsm),
shown by our team to substantially delay the onset of paralysis in MND
model mice. By determining the mechanism of action for CuII(atsm)
in detail our current research activities present a unique opportunity
to simultaneously progress the development of CuII(atsm)
towards clinical trials, and to identify what may be an important
biological contributor to all forms of MND.
Using funds received
from the MND Research Institute we have examined CuII(atsm)
activity in a range of cell types grown under conditions that simulate
the abnormal conditions that may cause motor neurone degeneration in the
spinal cord. We have focused on conditions that decrease the cell’s
capacity to generate its own energy supply and have found that these
conditions induce activation of the therapeutic potential of CuII(atsm).
Our research is in the
pre-clinical development of potential therapeutic compounds. This type
of research means that the strong positive outcomes we generate are in
reality still many years away from testing our compounds in people with
MND. However, the pre-clinical testing that we undertake is essential
for new compounds to have any chance to be effective when ultimately
given to people with MND.
We will continue our
pre-clinical testing of CuII(atsm)
as a potential new therapeutic for the treatment of MND. By determining
its mechanism of action in greater detail we will be able to progress CuII(atsm)
further towards clinical trials or develop derivative compounds with
improved therapeutic efficacy.
Zo-eč MND Research Grant
Dr Fiona
Fisher
Calvary Health Care
Bethlehem, VIC.
Emotion
recognition and social communication in MND: impact on behaviour and carer
burden.
Limited research has
shown that MND can damage parts of the brain that are essential for
normal understanding of emotions, and in particular in understanding the
non-verbal aspects of communication (i.e. body language) that provide
cues to help people determine the emotional states of others. What this
means is that some people with MND may have trouble with the finer, more
subtle aspects of social communication. This research project compared
performances of a group of persons with MND and a group of healthy
participants of a similar age and gender.
Results showed persons
with MND performed worse overall than healthy participants on measures
of social cognition (i.e. interpreting how others are feeling from more
subtle gestures and cues), but not on measures of basic emotion
recognition (i.e. both groups were well able to recognise common
emotions such as happy, sad etc.).
Video-taped
conversations between participants and researchers were rated by speech
pathologists, specialised in examining subtle aspects of social
communication. Overall, the MND group had more difficulties with social
communication than healthy participants. This was independent of their
level of physical disability.
Difficulties with social
communication and accurately perceiving emotional interactions with
others can have a negative impact on one’s ability to remain emotionally
connected to close others. Such difficulties may even affect the
appropriateness of a person’s behaviour in social situations which may
cause embarrassment or lead to social isolation. These changes have the
potential to strain relationships between persons with MND and their
carers. Therefore, by continuing to investigate ways these difficulties
can be recognised early, appropriate education and strategies can be
implemented.
Dr Robert
Henderson
Department of Neurology,
Royal Brisbane & Women's Hospital.
Novel
markers of motor neurone disease- quantitative upper and lower motor neurone
markers.
The underlying cause of
MND is unknown and there is no effective method of assessing disease
progression over time. Such a method would be useful as a measure in
clinical trials. MND involves death of upper and lower motor neurons
(the nerves that control motor function).
This project examines
upper and lower motor neurone markers. The lower motor neurone marker
uses an electrophysiological measure that can be applied to standard
nerve conduction studies (CMAP scan) with a software application using
Bayesian statistics. 44 MND subjects have been serially studied using
this measure. The data has been presented at international meetings and
there is interest in other centres using this method.
The upper motor neurone
marker diffusion tractography (DT), somewhat similar to having an MRI
scan, has been serially applied in 19 subjects and much of the MNDRIA
funding has been used to fund these studies. The work has been
presented at international meetings. Over the next 6 months the data
from the upper and lower motor neurone markers will be combined to help
understand the relationship between upper and lower motor neurone
degeneration. For MND subjects, this work will assist in understanding
the mechanisms of MND and could be applied in treatment trials.
Dr Qiao-Xin Li
Dept of
Pathology, University of Melbourne.
Investigating the in vivo targets affected by a novel
therapeutic agent for motor neuron disease.
Our
previous work has found that orally administrated CuII(atsm)
(an anti-oxidant compound) can substantially delay the development of
MND-like symptoms in an MND mouse model SOD1G93A and extend the life by
10% in mice with motor symptoms. Our current work is to test the
treatment effects of CuII(atsm)
in combination with Riluzole in the MND mice with motor symptoms, as
this reflects the current clinical situation in humans. We found that
the MND mice treated with CuII(atsm)
and Riluzole have a life span of 273 days, significantly longer than the
mice with single drug treatment by 11%. We have also treated another
MND mouse model, SOD1G37R, with CuII(atsm)
to see if the drug is effective in a different model. This treatment
started at pre-symptomatic age of 4 weeks. The SOD1G37R mice treated
with the drug have also lived longer than the mice without the drug.
This confirms that the drug is also effective in another model.
Since
the drugs were given to the mice after onset of symptoms, the result
will be directly relevant to clinical application, and will aid future
clinical trials. Although it is still a long way for the use of CuII(atsm)
as a more effective treatment for MND in humans, every outcome from our
project is a step closer to this ultimate goal.
The
fundamental research will lead to a better understanding of the
progression of MND and enable us to define whether the CuII(atsm)
work can be progressed to humans.
Dr Hakan
Muyderman
Medical Biochemistry & Human
Physiology
Flinders University, SA.
The role
of TDP-43 in astrocytes in motor neuron disease.
On the microscopic
level, MND is characterised by the presence of cellular structures known
as inclusion bodies. The major component of these structures is a
protein called TDP-43. Changes in the gene coding for this protein
(mutations) can cause an inherited form of the disease. Little is known
about how changes in the normal function of this protein, or how the
mutated forms, cause disease.
Recent results obtained
in our laboratory show that these mutations not only cause pronounced
effects on normal function of nerve cells, but also alter the function
of astrocytes, a specialised supporting cell type in the nervous system
that previously have been suggested to play an important role in the
development of MND.
In the present study we
are investigating the effects of TDP-43 mutations on the normal function
of motor neurons and astrocytes and determine if these mutations affect
the important interactions that normally takes place between these cell
types.
These studies are likely
to produce novel and important information of the development and
progression of MND and provide new approaches for treatment of affected
individuals.
A/Prof
Roger Pamphlett
Stacey MND Laboratory,
University of Sydney.
Looking
for abnormal gene expression in ALS spinal cords using next-generation
sequencing.
The basic genetic
pathway is that DNA (in genes) makes RNA, and the RNA then makes
proteins. Increasing evidence suggests RNA abnormalities may give clues
as to the cause of MND. A powerful way to uncover genetic abnormalities
underlying a disease is to extract RNA from the tissue most affected by
the disease (the brain or spinal cord in the case of MND), and see if
this differs from normal tissue. RNA can be abnormal in being (1)
decreased in amount, (2) increased in amount, or (3) of an abnormal type
(e.g., with a “misspelling”).
Until now, technological
limitations have restricted the measuring of RNA to a small number of
genes. The latest “next-generation” sequencing methods, however, can
examine all the “messenger” RNA (the RNA that makes the proteins) from
the entire human genome (all the 25,000 genes). We have therefore set
up an international collaboration with The Genome Center at Washington
University to look for RNA abnormalities in people with MND who have
donated tissues to Australian MND brain banks.
We have so far completed
all the complex ethical and legal requirements that are needed for an
international collaboration that uses human tissues. We have sent the
frozen tissues over to Washington University for analysis. The
Washington University team are now assessing which of the spinal cord
samples we sent are most likely to give positive results on the RNA
testing. The final step will be to undertake the complex statistical
analyses on the data obtained to see which RNA is truly abnormal in MND.
By telling us which
genetic defects underlie MND, we hope these findings will have a direct
bearing on future gene therapy in MND.
Dr
Mary-Louise Rogers and Prof Robert Rush
Dept of Human Physiology,
Flinders University SA.
A
bio-marker for motor neurone disease.
An important step in
finding effective treatments for MND is to identify biomarkers in animal
models of MND that can be used in assessment of potential new
treatments. We have preliminary data from the SOD1G93A mouse model of
MND that indicates this is achievable. Motor neurons respond to disease
by up-regulating various proteins on their nerve terminals; many of
these are then shed into body fluids, appearing in both serum and
urine. We have evidence that one of these proteins, the neurotrophin
receptor p75 (p75NTR) is present in urine of SOD1G93A mice but not
age-matched control mice. The aim of this project was therefore to ask
if p75NTR is a potential biomarker for MND. Specifically, we tested the
hypothesis that the appearance of p75NTR protein in urine provides value
as a biomarker for MND.
We have found that the
p75NTR protein in urine can be used to diagnose MND in the SOD1G93A
mouse model of MND well before any symptoms are present. The appearance
of this 'biomarker' of the disease in urine of mice will be valuable as
a way to identify the effectiveness of new treatments of this
devastating illness. The next stage of our research is the development
of a sensitive assay that can detect p75NTR in both serum and urine and
can be used to monitor MND treatments in both SOD1G93A mice and humans.
Dr
Bradley Turner
Florey Neuroscience
Institutes, University of Melbourne.
A role
for survival motor neuron protein in MND?
This project examined
whether SMN, a molecule important for motor neurons, is abnormal in
people with MND. This extends our previous work showing that SMN is
extremely low in test tube and mouse models of MND. In this funded
project, we have discovered that SMN levels are drastically lower in
spinal cords from MND patients compared to normal people. This is an
important step because it suggests that low levels of SMN may increase
risk for MND. This could also shed some light on what causes MND. Our
findings also imply that supplementing SMN may be possibly helpful in
MND. We will continue to test whether SMN supplementation in MND mice
is beneficial using genetic and drug approaches.
If our proposal is
supported, then these results could pave the way for future studies to
find, develop and test strategies to supplement SMN in MND.
Charles and Shirley Graham MND Research Grant
Dr Robyn
Wallace
Queensland Brain Institute.
Identifying genes that are affected by MND causing TDP-43 mutations.
Protein tangles that
aggregate in affected nerve cells are a pathological hallmark of MND.
Recent studies have demonstrated that TAR DNA-binding protein (TDP-43)
is a principal component of these nerve cell aggregates. TDP-43 is
known to regulate other genes in the nervous system but the actual genes
it regulates are largely unknown and the role of TDP-43 in MND remains
unclear. The aim of this project was to identify genes that are
regulated by TDP-43 and to determine whether these genes are altered in
MND patients with TDP-43 mutations.
Using mouse tissue, we
have isolated over 2,000 potential gene targets of TDP-43. The targets
included 3 genes that have previously been implicated in MND, providing
a link between TDP-43 aggregation and familial MND. We have also
discovered that many of the TDP-43 target genes are involved in
controlling signals between nerve cells and muscles.
We next used the
techniques we optimized in the mouse tissue to analyse nerve cells from
an MND patient with a mutation in the TDP-43 gene. We discovered that
the mutation reduces the ability of TDP-43 to bind to certain target
genes, including the 3 MND genes identified in the mouse study. The
loss of target gene binding due to the TDP-43 mutation also included
several genes that are normally responsible for nerve cell survival,
providing key insights into why nerve cells die in MND patients.
These studies are
improving our understanding of what causes MND and in the future will
provide rational targets for the development of new therapies.
Mick Rodger Benalla MND Research Grant
Dr
Anthony White
Dept of Pathology,
University of Melbourne.
Investigating the role of biometals in abnormal metabolism of TDP-43.
Little is known about
the causes of motor neuron disease. Recent studies have identified a
key role for a protein called TDP-43 in MND and in some cases of
frontotemporal dementia. While some advances in understanding TDP-43
processing during disease have been made through analysis of genetic
mutations, very little is known about the changes that occur to TDP-43
in sporadic MND, which accounts for more than 90% of all cases.
Neurodegenerative diseases including MND are known to have important
roles for increased chronic oxidative stress and altered metabolism of
biometals such as zinc, copper and/or iron. Our studies have been
investigating the role of these factors (oxidative stress and biometals)
on processing of endogenous (non-mutated) TDP-43 to try and understand
the early changes to the protein that may precipitate neuronal
dysfunction in MND. Our studies have found that altered zinc levels and
more recently, oxidative and nitrogen-based (nitrosative) stresses are
associated with robust changes to TDP-43 in neuronal cell cultures.
These changes closely re-capitulate the changes to TDP-43 observed in
the brains and spinal cord of MND and frontotemporal dementia and
include loss of TDP-43 from the nucleus of neurons (where it normally
resides), accumulation and aggregation in the cytoplasm of cells,
association with stress granule proteins (sites of RNA protection),
formation of short C-terminal fragments and ubiquitination of the
aggregates (indicating the formation of irreversible protein
aggregates). These are all hallmarks of TDP-43 in MND and our studies
indicate that induction of chronic nitrosative or oxidative stresses,
possibly related to altered metal metabolism can induce these effects in
neurons in sporadic disease. We are currently investigating how this
process occurs and our studies indicate a role for altered cell
signaling processes controlling aggregation of TDP-43. We have also
found that a potentially therapeutic compound (CuII(atsm)) can prevent
this aggregation process and may offer a therapeutic intervention in
MND.
The
Motor Neurone Disease Research Tissue Bank of Victoria
The
Motor Neurone Disease Research Tissue Bank of Victoria (mndRTBv)
established in 2003 is a dedicated repository of central nervous system
(CNS) samples such as fluids (blood and cerebrospinal fluid {CSF}) and
brains and spinal cords obtained from people diagnosed with MND. From
these samples, the neuropathologist is able to confirm diagnosis of the
disease. More importantly, these samples are then prepared to
facilitate their use in histological, proteomic, genomic and biochemical
studies and are made available to Australian and International
neuroscience research communities to further investigate MND. Our aim
is to enhance MND research and encourage new researcher involvement.
Providing researchers with access to high quality, well-characterised
(of an international standard) CNS tissue and related samples has
facilitated research opportunities into MND. This has the potential to
maximise important discoveries, which may lead to improvements in
diagnosis, development of early diagnostic tests, therapeutic
interventions and/or development of preventative strategies.
Furthermore, having such a vital resource available in Australia
eliminates the need to access tissue from overseas at great financial
expense and time delay.
Since
the inception of the
mndRTBv,
tissue has been provided to 18 new or continuing projects which equates
to 259 tissue samples. Research projects have been conducted by
research groups at The University of Melbourne, Florey Neuroscience
Institute, Latrobe University and The University of Sydney. This work
so far has lead to 15 Australian and International publications and
presentations.
As a
not for profit research facility the funds received from the MND
Research Institute go some way to supporting the day to day operations
of the
mndRTBv
and
to assist with associated tissue collection and processing costs.
The
mndRTBv
would
like to acknowledge the generosity shown by the donor and donor families
in donating tissue to the
mndRTBv.
It is an act of great foresight and kindness to give at a time of loss,
so that others may be helped in the future.
The
operations of the
mndRTBv
have
the generous financial benefit of using the existing infrastructure and
facilities already in place within the Victorian Brain Bank Network (VBBN)
which leads to substantial cost savings. The benefits include the
salary support of the VBBN administration, clinical and scientific staff
and infrastructure costs related to building space occupied, property
services, IT support, communication systems, administration support,
insurance, financial and accounting support, stationary, printing,
postage etc and laboratory services; tissue processing, tissue
distribution, equipment use and consumables.
The
VBBN and
mndRTBv
are
part of the Australian Brain Bank Network, an internationally
acknowledged Brain Banking Network.
The total number of MND cases available through the
mndRTBv
and the ABBN is now 114. The following websites provide
Australian and International researchers with details of diagnostic
categories, number of cases available and a central point of contact to
access tissue -:
· MND
Research Tissue Bank of Victoria:
http://www.mndtissuebank.asn.au/
· Victorian
Brain Bank Network:
http://www.mhri.edu.au/VBBN.htm
· Australian
Brain Bank Network:
http://www.nnf.com.au/abbn/
We continue to work towards increasing the number of
blood, cerebrospinal fluid, brain and spinal cord donations through
dissemination of information. Avenues for raising awareness are through
announcements in the MND Association of Victoria newsletter, clinicians,
word-of-mouth, and a brochure that has been devised for potential
donors.
Professor Catriona McLean
Mental Health Research Institute, Victoria
Postdoctoral Fellowships
Dr Anna King
(2008-2010)
University of Tasmania.
Investigating causes & consequence of axonal pathology in
ALS.
Nerve
cells or neurons are highly specialised and unique cells that have long
nerve processes, which are responsible for transmitting signals around
the body. Motor neuron disease (MND) is caused by a loss of a specific
class of nerve cells, termed motor neurons, which control the muscles.
Motor neurons can have very long processes (axons), which can constitute
up to 99 percent of the cell. Although we know that motor neurons die
in MND, there is evidence that before they die there is a time where the
cells are not functioning properly because the nerve signal is not being
transferred along the nerve process to the muscle.
We think that protecting the nerve process and restoring
function is a potential point of therapeutic intervention for MND,
either alone or in combination with therapies that protect the cell body.
Before therapeutic intervention can be developed we need to find out
what is going wrong with the nerve process or axon. The nerve processes
of motor neurons extend from the spinal cord to the muscles. When nerve
processes in the spinal cord are examined under the microscope they
frequently appear to have large swollen structures. The nerve processes
in muscle frequently have a type of pathology termed ‘dying back’
pathology where they appear to no longer connect to the muscle and so
cannot stimulate it.
During my Bill Gole Fellowship I have studied these
changes in the axons of motor neurons and looked at mechanisms that can
cause these types of changes to occur. Furthermore I have determined
how these changes affect the normal function of the neuron.
To examine nerve cell axons in detail I have developed techniques to
grow motor neurons in a dish so that I can expose them to different
conditions that may be present in MND and find out what causes the
processes to become swollen and to lose their connections with muscle
cells. Using these techniques, I have shown for the first time that the
swollen nerve processes, similar to those in MND, may be caused by
changes to the cells that normally support the neurons. These
supporting cells are known to be important in the development of the
disease. I have shown that supporting cells that were old or that had a
mutation that causes MND result in more of the nerve processes becoming
swollen and this may be why MND develops with age.
To
examine more closely what was happening to the nerve processes I
investigated the proteins and structures within the cell. I found that
within the swollen parts of the axons the proteins that are usually
responsible for the cells’ scaffolding (cytoskeleton) were highly
disrupted and had accumulated. This was similar in the cell culture
model and also in a mouse model of MND. Another important aspect of
this work was to look at how these swellings affected the function of
the nerve cells. I performed live imaging experiments that demonstrated
that these swellings did not cause the cells to die rapidly, but rather
the movement of components around the cell was slowed. This may result
in distal parts of the cell being ‘starved’ and subsequent loss of
connection with the muscle.
My
previous studies have suggested that loss of connection between the axon
and muscle can also be caused by a pathological process called
excitotoxicity, where the cell becomes over activated. The Bill Gole
Fellowship has enabled me to develop a number of new techniques and
models that have contributed to the securing of further funding to
expand and continue this project in the future. Our next step is to
examine in more detail the changes that are occurring as the nerve
process dies back from the muscle and to determine the role of
excitotoxicity and support cells in this process. We will do this in
both animal and cell culture models. Our studies will also focus on
examining the therapeutic potential of protecting the nerve processes in
MND and we are currently studying the protective effect of stabilising
the cell cytoskeleton.
Despite disappointing therapeutic trials in MND to date, there has been
a substantial increase in our understanding of the underlying biology of
the disease in recent years. We hope that our approach of looking at
the functional structures of the motor neuron, such as the nerve
process, will aid in the development of strategies that will protect and
repair the damaged cells.
Dr Jennica Winhammar
(2008-2010)
Neuroscience Research Australia, University of NSW.
Clinical trial to assess the neuroprotective properties of a
sodium channel blocking agent in motor neurone disease.
Nearly 150 years have passed since Charcot defined Amyotrophic Lateral
Sclerosis (ALS) and there remains no cure, with riluzole, the only
disease-modifying therapy available to slow disease progression. There
is evidence of an increase in sodium entering motor neurons in ALS,
which may play a key role in their degeneration.
Our
aim was to undertake a double blind, randomised clinical trial to
evaluate whether ALS disease progression may be attenuated with a sodium
channel-blocking agent. ALS patients were consecutively recruited and
numerous outcomes were measured at each visit such as the respiratory
function tests, walking tests, muscle strength and functional scales.
In addition, new nerve excitability techniques were undertaken to assess
the direct effects of the medication on a neuronal level. The trial has
been completed and the data is currently being analysed.
Dr Justin Yerbury
(2009-2011)
University of Wollongong.
Probing molecular mechanisms of microglial and astrocyte
activation in ALS.
Recent evidence suggests
that motor neurone degeneration is an orderly and propagating process
that moves from one part
of the nervous system to other nearby locations. All forms of MND are
associated with piles of protein junk called inclusions and also with
inflammation of the brain. These protein junk piles can be found in the
motor neurones of all MND patients.
I am
investigating the possibility that these misshapen proteins found in the
junk pile are somehow passed on from one cell to another causing
dysfunction of neurones. We have observed this process occurring in
neuronal cells in culture dishes. This process mimics an infection in
that it can be passed from one cell to the next. We have also shown
that these protein aggregates or ‘junk piles’ are recognized by the
brains immune system and trigger it in to action. It is hoped that if
we can identify the way that cell death and dysfunction is “passed on”
from neurone to neurone, or the mechanism by which the immune system
recognizes these molecules we can design a much needed therapeutic.
Dr Shu
Yang
(2010-2012)
ANZAC
Research Institute, NSW.
Investigating the role of recently identified mutant genes in MND
pathogenesis.
Motor neuron disease is
a devastating neurodegenerative disorder caused by death of the nerve
cells controlling the voluntary muscles. MND patients experience a
series of emerging symptoms including progressive limb muscle weakness,
speech and swallowing difficulty and eventually respiratory failure.
The disease is often fatal within 2-5 years of diagnosis. The majority
of MND patients are sporadic, but approximately 10% of the patients have
a family history. The mechanism underlying MND is unknown. Gene
mutations are the only proven causes. In 2006, the TAR DNA binding
protein 43 (TDP-43) was identified for the first time as a major
component of the protein aggregates found in MND patient brains and
spinal cords. Our laboratory found several mutations in MND genes
including
TDP-43 and
FUS,
from MND patients. However, it remains unclear how these defective
genes cause MND. We found that short-term expression of these genes in
nerve cells grown in the laboratory reproduced features seen in MND
patient brain and spinal cord cells, e.g. protein aggregation and
mislocalisation. We found that mutations in the
TDP-43
gene caused more cell death than the normal
TDP-43
gene in neuronal cells. The mutations in the
TDP-43
gene also led to more TDP-43 mislocalisation, indicating that there may
be correlations between protein mislocalisation and development of MND.
Our preliminary data also suggested that mitochondria (the cell’s energy
factory) and key molecules of cell death, e.g. caspases, have been
involved in TDP-43 related cell death. We are now investigating the
long-term effects of these genes in nerve cells. This will help us to
identify specific cell functions that are affected by these defective
genes and also allow us to find differences between mutant and normal
genes. Further investigations are underway to study how these defective
genes cause motor neuron death as a prerequisite to the development of
treatments.
2009 Research Grants
The following reports provide information about the
projects funded by the MND Research Institute of Australia in 2009.
Grants-in-aid
Dr
Julie Atkin
Howard Florey Institute, University
of Melbourne.
New therapeutic approaches for MND
based on ER stress inhibition.
Unfortunately there are no
treatments that prevent or cure MND and hence effective therapies are
required. We recently showed that a cellular pathway called ‘ER stress’
triggers the death of motor neuron cells in MND. More importantly, we
and others have shown that
(i) ER stress occurs very
early in the disease process, prior to the onset of symptoms, suggesting
that it is an active, early and important part of the process that kills
nerve cells in this disease
(ii) ER stress occurs in
humans with the most common form of MND, sporadic disease.
In this proposal we wished to
determine if a new drug called BMC which blocks ER stress could be used
to delay disease onset and progression of this disease in motor neuron
cells in culture and in animals that develop MND.
Outcomes of this study:
1. We found that the drug was
protective against the toxic effects which occur in motor neuron cells
in MND.
2. More importantly, in the most
widely accepted model of disease, SOD1G93A mice, animals that
were treated with BMC had delayed symptoms and lost significantly fewer
motor neurons compared to untreated animals, demonstrating that this
drug is protective against the death of motor neurons in MND. This
study has opened up novel and exciting therapeutic targets for human MND
and gives support to the hypothesis that ER stress is an important
target in this disease. This drug will be taken further in future
studies to explore its potential in MND.
Peter Stearne Grant for Familial MND Research
Dr
Ian Blair
ANZAC Research Institute, NSW
Identifying novel genetic loci for familial motor neuron disease.
The only proven causes of MND are mutations in genes that lead to death
of motor neurons. However, the known MND genes only account for about
20% of familial cases (2% of all MND cases). Our long-term goal is to
gain an understanding of the biological basis of MND through
identification of genes that cause the disease among the majority of MND
families for which no gene has yet been identified. We have recruited
over 80 MND families in which the responsible gene is unknown. The aim
of this project was to use genetic screening strategies in a subset of
our MND family cohort to identify one or more chromosomal regions that
harbour new MND genes. In collaboration with Prof C Shaw (Kings College
London) mutations were identified in a new MND gene called FUS.
Although these mutations are rare among MND cases, the finding is
significant because FUS is closely related to another MND gene, TDP-43.
Together, these genes implicate a common biological process underlying
the disease. Work has now commenced to understand that process. We
also anticipate that further genes will be identified among the families
under study. Identification of the genes causing MND will lead to a
greater understanding of the biology of motor neurons and the basis of
familial and sporadic motor neuron degeneration. This understanding is
a prerequisite to effective diagnosis, treatment and prevention of the
disease.
Identification of new genes will have implications for both MND research
and diagnostics. New gene tests will be developed to add to those
already screened among MND cases with a family history. New MND research
will stem from the discovery of new disease genes, including the
development of new cell and animal models that will help accelerate the
search for therapies.
MND Victoria Research Grant
Dr Fiona Fisher
Clinical Neuropsychologist,
Calvary Health Care Bethlehem, VIC
Cognitive and Behavioural changes in MND:
exploring the impact on caregivers.
While in the past Motor Neurone Disease has been thought
to predominantly affect the body, more recent research has noted that a
small proportion of persons with MND experience changes in the way they
behave and interact with others, and/or in the way they think, make
decisions and recall information. In such instances, the team at the
Calvary Health Care Bethlehem (CHCB) MND Clinic have observed an
increased emotional and physical load on carers and family members,
particularly in situations where the person with MND is not aware of
such changes.
The current project aimed to see how often behaviour and
cognitive changes were present, and also identify the behaviour and
cognitive changes most challenging for caregivers.
It is anticipated that
subsequent research programs will look toward the development of
interventions and/or education programs to support caregivers, aimed at
reducing caregiver distress and promoting improved quality of life for
both the persons with MND and their caregivers.
Mick Rodger Benalla MND Research Grant
Dr
Anna King
Menzies
Research Institute,
TAS.
The
role of distal axonal degeneration in ALS.
Amyotrophic lateral sclerosis (ALS), the major cause of
motor neuron disease, is a devastating disease resulting in muscle
paralysis through loss of the nerve cells controlling the muscles. Nerve
cells are highly specialised cells, which have long processes (axons)
that are necessary for the conduction of impulses from the central
nervous system to the nerve terminals at the muscle. It is still
unclear whether this disease is caused by a dying back from these nerve
terminals at the muscles, or a dying forward from the cell bodies in the
spinal cord or brain. This question is critical to the provision of
therapeutic intervention. This proposal seeks answers to this important
question using animal and cell culture models. A primary goal for this
research project is to establish techniques and provide preliminary data
for a major NHMRC project grant application in this area. Support from
the Motor Neuron Research Institute has enabled collection of data that
will form the basis of an NHMRC grant application for 2011.
Charles & Shirley Graham MND Research Grant
Dr
Marina Kennerson
ANZAC Research Institute
NSW
Finding genes causing familial motor neuron degeneration.
Our
laboratory
has
led
and coordinated
an
international
collaboration for
identifying
a gene causing a
familial
form
of
distal
spinal muscular atrophy
on the X chromosome (DSMAX).
Through funding from the MNDRIA
the
laboratory
has
undertaken
state-of-the-art
molecular
methods
to
examine the region of DNA on
chromosome
X containing
the
gene mutation. We
have identified the causative gene responsible for
DSMAX
which
has
been submitted for
publication. The
gene
identified
when mutated causes the mutant
protein to
traffic
incorrectly
(ie.
it
does
not
locate
to
the correct region in
the
cell). Several mutations have
been identified
in
this
gene
in
unrelated distal
spinal muscular
atrophy
families.
Identification
of
this
gene
will
help to
elucidate the
importance
of
the
correct trafficking of the newly
discovered protein
in motor neurons
and provide the opportunity for the development of
treatment
intervention
for
patients with the mutation
that can correct the
movement
of the protein in the patient
motor
neurons.
Now
that
the gene
has
been
identified
this
will
allow us to develop disease models to understand the
progressive
death
of motor
neurons
and axonal
degeneration that occurs with the newly identified mutant
protein.
This
has
important
implications for
rapidly
progressive forms of motor neuron disease as axonal
degeneration
is observed
in
the early stages
of
ALS.
This project has demonstrated the importance of
examining
slowly
progressive
motor neuron
disorders in which
gene
identification
in these families
facilitates
our
understanding of
motor neuron
biology and the
important pathways
involved in their
maintenance.
Zo-eč MND Research Grant
Dr
Louisa Ng
Rehabilitation
Physician,
Royal Melbourne Hospital, VIC
Disability in
motor
neurone
disease.
This research project describes the disability experience and needs of
MND from the perspective of the people with MND themselves and from
their caregivers. This enables health professionals managing MND to be
better informed with the aim of providing improved treatment/management.
44 persons with MND (pwMND) and 37 caregivers were recruited through a
large tertiary multidisciplinary centre and interviewed. A similar
interview was used for all participants (pwMND and caregivers). An
open-ended questionnaire with the single question, “what are the main
problems you face in your everyday life” was asked, followed by a series
of questionnaires on self-reported perceived needs for services and
actual services received, anxiety, depression and stress, quality of
life and coping strategies. In addition, caregivers were asked to rate
their burden of care on a 0-100 scale.
Data from the questionnaires is still being analysed but preliminary
findings include:
· Doctors
may underestimate the issues of pain and spasticity/cramps/spasms.
· Psychosocial
support may be an area of need that should be further explored.
· Many
of the disabilities reported are amenable to rehabilitation
treatment. This reinforces the recommendation by the European
Federation of Neurological Societies that pwMND be able to access
multidisciplinary rehabilitation services.
· Many
issues with hobbies/leisure activities and socialising are amenable
to technological advances currently available. More consideration
of the use of such technology could facilitate these activities
· It
was noted that in general, most participants were very satisfied
with their current level of services. This is likely attributed to
the multidisciplinary care that they receive and also to the close
links between their health care provider and MND Association of
Victoria which provided many of their equipment and advocacy needs.
· Interventions
such as determining service needs from the caregivers perspective
are necessary to reduce poor outcomes among both caregivers and care
recipients with MND.
In using the International Classification of Functioning, disability and
health (ICF) to describe the problems and the impact of the problems
that the MND population faces, it will be possible to compare the
experiences of the MND population in Australia to the international
perspective.
Dr Steve Vucic
Prince of Wales Medical Research Institute, NSW.
The role
of fatiguing exercise in the aetiology of MND.
Clinically, ALS is characterised by muscle weakness and wasting,
together with upper motor neuron features of brisk reflexes and
increased tone. In addition, fatigue is a prominent symptom in MND.
The mechanisms underlying the development of neurological features, as
well as fatigue, remain elusive. Recently, studies have suggested that
there is a link between fatiguing exercise and development of MND,
although the precise mechanisms mediating this association remain to be
fully elucidated.
The current project was designed to investigate whether changes in
cortical excitability in MND patients develop after fatiguing exercise
and whether they are linked to the perception of fatigue as measured by
the modified fatigue impact score. MND patients were recruited from the
multi-disciplinary MND clinics at Prince of Wales and St Joseph’s/Westmead
hospitals. All studies were performed at the Prince of Wales Medical
Research Institute, Randwick.
This project builds on previous studies in MND patients which suggest
that fatigue may be a process generated in the peripheral nervous
system. By dissecting out relative contributions from the upper and
lower motor neurons to the development of fatigue, therapeutic
strategies could be implemented to overcome this debilitating symptom.
Of further relevance, a potential causal relationship between exercise
and neurodegeneration may be established which would in turn guide
physical therapy. Future studies should assess the impact of varying
levels of exercise intensity on fatigue and cortical excitability in
MND.
Postdoctoral Fellowships
Dr Anna King
Menzies Research Institute,
University of Tasmania
Bill Gole Postdoctoral MND
Research Fellow 2008-2010
Investigating the causes and consequence of axonal pathology in amyotrophic
lateral sclerosis.
Motor neuron disease (MND) is caused by a loss of function of the nerve
cells controlling the muscles. The nerve processes in ALS are
frequently swollen with accumulations of proteins and this may be
responsible for their loss of function. However the cause and
consequence of these swellings is unclear.
I have developed a cell culture model that mimics these degenerative
changes in motor nerve cells, and have found that this pathological
feature is influenced by the health of the surrounding support cells. I
am using this model to investigate the factors and mechanisms that cause
motor neurons to degenerate, which may indicate new therapeutic
opportunities for an otherwise incurable condition.
Dr Jennica Winhammar
Prince of Wales Medical Research Institute, NSW
Bill Gole Postdoctoral MND Research Fellow 2008-2010
Clinical trial to assess the neuroprotective properties of a sodium channel
blocking agent in MND.
This project will provide clinical trial information related to the
potential neuroprotective properties of a sodium channel blocking agent
in patients with motor neuron disease. Specifically, it will establish
whether this trial medication can slow disease progression. A potential
therapeutic response would provide impetus for a larger scale,
multi-centre clinical trial. In addition to providing information about
potential mechanisms of neurodegeneration and their treatment, new
quantifiable measures will be further developed to objectively monitor
MND patients in a clinical trials setting.
Clinical Trial
This trial is now over half way to completion. The clinical trial
protocol has been finalised and recruitment has been very successful.
27 patients have completed the trial. There are 26 patients in the trial
at present, most of them have completed the lead in phase and have
started taking the trial medication/placebo. No major adverse effects
have been reported and the drug seems to be well tolerated. More data
analysis on the trial will be carried out when the trial is complete as
we are still blinded and do not know who is on medication and who is on
placebo.
Dr
Justin Yerbury
Centre for Medical Biosciences,
University of
Wollongong.
Bill Gole Postdoctoral MND Research Fellow 2009-2011
Probing molecular mechanisms of microglial and astrocyte activation in ALS.
Recent evidence suggests that motor neurone degeneration is an orderly
and propagating process that moves from one part of the nervous system
to other nearby locations. All forms of MND are associated with piles of
protein junk, called inclusions. These can be found in motor neurones
and another non-neuronal cell type – astrocytes. Only astrocytes that
are close to motor neurones have these inclusions. I am investigating
the possibility that these broken proteins in the junk pile are somehow
passed on from one cell to another causing dysfunction and cell death
along the way. It is hoped that if we can identify the way that cell
death and dysfunction is “passed on” from neurone to neurone we can
design a much needed therapeutic.
NHMRC / MNDRIA PhD Scholarship 2009 - 2011
Dr James Burrell
Prince of Wales Medical Research Institute, NSW
Cognition and behaviour in motor
neuron disease.
As MND progresses, some patients may develop changes in
language, personality or behaviour that resemble those symptoms seen in
patients with frontotemporal dementia (FTD). Similarly, a significant
minority of patients with FTD may develop MND.
Recent discoveries in pathology and genetics have
reinforced the concept that MND and FTD are two extremes of a single
disease continuum.
This project aims to understand these overlaps and to
assess other components of cognitive and motor system performance in
both patient groups.
Clinical assessments, including a novel test of tool and
gesture usage, will be combined with neurophysiological investigations
aimed at identifying and characterising motor neurone dysfunction, both
in the brain and at the level of the spinal cord. These measures are
being correlated with results of formal cogntive testing. Eye movements
are also being tested using equipment designed specifically for the
purpose. A clear undertanding of cognitive symptoms and the relationship
of MND to FTD is crucial, not just to increase the basic understanding
of MND, but also to highlight the potential impact cognitive symptoms
have on patients with MND, their carers and patient management.
2008 Research Grants
The following reports provide information about the
projects funded by the MND Research Institute of Australia in 2008.
Grants-in-aid
Dr
Julie
Atkin,
Howard Florey
Institute, University of Melbourne
Is Endoplasmic Reticulum stress primarily responsible
for cell death in Motor Neuron Disease
We have recently found that a
compartment of the cell previously unexplored in MND, the
‘endoplasmic reticulum’, or ‘ER’ is stressed in affected tissues of
animals and humans that develop MND. This is an important
observation as it offers novel directions for research, but we
currently do not understand the precise cascade of events that
result in motor neuron death.
In this proposal we have been able to
characterise in detail the events leading up to stress in the ER. We
have discovered that this ‘ER stress’ occurs very early in the
disease process and hence it is likely to play an important role in
pathology. ER stress also occurs prior to the abnormal protein
inclusions that are observed in MND and other neurodegenerative
diseases, and our data suggests that the ER stress may even trigger
the formation of these inclusions. These studies reveal that ER
stress is a good target to trial new therapies for MND. We are
therefore currently trialling new molecules based on ER stress in
the SOD1 mouse model of MND, to determine if they delay disease
onset or prolong survival.
Dr
Mark
Bellingham,
Department of
Physiology and Pharmacology, University of Queensland
The molecular and functional basis of
motor neuron hyper-excitability in an animal model of motor neuron
disease
The aim of this project is to determine why motor neurons show
hyper-excitability in an animal model of motor neuron disease. We
will compare the excitability of hypoglossal motoneurons in normal
mice and in transgenic mice over-expressing normal or mutated human
superoxide dismutase-1 (SOD1), a commonly used animal model of motor
neuron disease. We will correlate hyper-excitability with the
level of the persistent sodium current, an ion current which is a
key controller of motor neuron excitability, and with measurements
of gene and protein expression for specific sodium channels, to
determine why hyper-excitability occurs.
This project will improve our understanding
of the underlying causes of motor neuron disease, by providing
information about how differential expression of specific sodium
channels in motoneurons is correlated with the
hyper-excitability in these motoneurons prior to their ultimate
death.
Dr Ian Blair,
ANZAC
Research Institute, NSW
Peter Stearne Grant for Familial MND Research
Identifying new genes for familial Amyotrophic Lateral Sclerosis
The only proven
causes of ALS are mutations in genes (including SOD1 and TDP-43
genes) that lead to death of motor neurons. However, the known ALS
genes only account for about 20% of familial cases (about 2% of all
MND cases). Our long-term goal is to gain an understanding of the
biological basis of ALS through identification of genes that cause
the disease among 80% of ALS families for which no gene has yet been
identified. We have recruited over 100 ALS families in which the
responsible gene is unknown. We screened these families using
high-throughput genetic techniques to identify shared chromosomal
regions that harbour previously unknown ALS genes. This analysis has
implicated several chromosomal regions. Potential candidate genes
were identified on these chromosomes and screened for mutations. In
a collaborative investigation with Kings College London, a new gene
causing ALS has been identified. This gene represents the second
most common known cause of familial ALS. Work is now underway to
understand how this defective gene causes the death of motor
neurons. Identification of the genes causing MND is leading to a
greater understanding of the biology of motor neurons and the basis
of familial and sporadic motor neuron degeneration. This
understanding is a prerequisite to effective diagnosis, treatment
and prevention of the disease.
We are undertaking
large scale genetic linkage studies to identify positional candidate
genes to be screened for mutations among our large familial ALS
cohort. We are also identifying functional candidate genes for
mutation analysis. In collaboration with Christopher Shaw’s research
group at Kings College London, linkage studies have identified
strong evidence for the presence of new ALS genes on chromosomes 9,
16 and 20. We have recently linked five families to one of these
loci. One of these large families comprises over 100 individuals
from whom we have now collected 72 DNA samples. A mutation in a
functional candidate gene that was identified from one of the linked
intervals was identified in this large family. This mutation
segregates with disease and is absent in a large number of control
individuals. Genetic analyses in families with mutations confirm
linkage to this gene locus. Mutations in this gene have now been
identified in four other Australian families from our cohort and
account for approximately 4% of familial ALS in Australia. This gene
represents the second most common known cause of familial ALS. This
mutated protein is functionally related to TDP-43, which is widely
pathogenic in familial and sporadic ALS. Identification of another
related molecule is exciting and implicates a common pathological
mechanism in the pathogenesis of ALS.
We performed a
high-throughput screen for mutations in this new ALS gene in 246
sporadic ALS cases. No mutations have been identified in sporadic
ALS cases, suggesting that mutations in this gene are unique to
familial ALS.
We are now cloning
mutant cDNA for future investigation of the functional consequences
of the identified mutations.
The new
gene mutation is described briefly below:
Another new MND gene mutation (FUS)
discovered in some families with familial MND
Two
reports published simultaneously in the journal
Science on
27
February 2009 describe mutations that have been identified in
the gene encoding fused in sarcoma (FUS). One study describes
FUS mutations found in Australian and UK MND families; the other
reports FUS mutations in North American MND families.
FUS
mutations account for between 3% and 5% of MND families. As
such, FUS is the second most common known cause of MND after
SOD1. However, a substantial significance of this discovery
lies in the functional similarity of the FUS protein with
TDP-43, a protein previously shown to be abnormal in MND.
Abnormal TDP-43 pathology is thought to be present in over 90%
of all MND cases (sporadic and familial MND combined). In
contrast, SOD1 pathology only accounts for about 2% of all MND
cases. Until now, the known MND genes (including SOD1, TDP-43
and ANG) had diverse and seemingly unrelated functions. It has
been difficult to identify a common defective mechanism
underlying motor neurone degeneration. With the discovery of
abnormal FUS in MND, a common defective mechanism has been
identified. Both FUS and TDP-43 are RNA binding proteins that
are thought to process and transport RNA. They both normally
reside in the nucleus of the cell. In the affected motor
neurones of most MND patients, TDP-43 is shuttled out of the
nucleus to the cytoplasm where it forms aggregates. This same
process has been found to occur with FUS in MND patients who
carry a FUS mutation. Research efforts can now focus on this
common defective mechanism to better understand the disease
biology and ultimately give insights into new therapies that
target that defective process. Development of cell and animal
models based upon mutant FUS should help accelerate the search
for therapies.
This work was made possible by the dedicated cooperation of
families with inherited MND. In Australia, the work was
supported by the National Health & Medical Research Council and
the Peter Stearne Grant for Familial MND from the MND Research
Institute of Australia.
Dr Robert Henderson,
Department of Neurology, Royal Brisbane & Women's Hospital, Queensland
Measuring Disease of Upper and Lower Motor Neurons in Amyotrophic
Lateral Sclerosis (ALS)
This project aims to
map the progression of ALS (also known as motor neurone disease
(MND) in Australia). We have performed a relatively new technique
to assess brain activity to the spinal cord to make muscles function
(assessing upper motor neurons), through diffusion imaging (DI)
(similar to magnetic resonance imaging (MRI)). We have also
concurrently assessed the activity from the spinal cord to the
muscles (lower motor neurons), where we are performing electrical
stimuli activity over the muscle nerve in order to count the nerves
remaining to a muscle – this is known as motor unit number
estimation (MUNE). This testing is performed every six months for
approximately 24 months. The study is being done to determine an
accurate measure to monitor disease progression and attempt to find
out more information about the disease.
So far we have
recruited 5 participants diagnosed with MND and 3 normal healthy
control subjects (the study aims to recruit 8 participants with MND
and 8 normal healthy controls. We have analysed the data and
qualitatively compared the DI findings with the clinical findings.
We are in the process of determining the quantitative information
for both the DI and MUNE. We are enlisting the help of Professor
David Reutens for this part of the project.
We continue to
recruit both MND participants and normal healthy controls towards
the study numbers. We continue to monitor the participants at the
allocated time points i.e. six month repeat DI and MUNE is ongoing.
If we were better
able to understand the disease and were able to monitor its
progression, then we would be in a better situation to perform
clinical treatment trials on a group of MND patients to either treat
or cure MND.
Anne
Horne-Thompson,
Calvary Health Care Bethlehem, Victoria
MND Victoria Research
Grant
An
investigation comparing the effectiveness of a live music therapy
session and recorded music in reducing anxiety for patients with
amyotrophic lateral sclerosis/motor neurone disease.
This study came about
as a result of clinical work undertaken at Calvary Health Care
Bethlehem. A number of patients with motor neurone disease were
being referred to the music therapy program specifically to address
issues of anxiety. In fact, this was one of the most common reasons
for referral to music therapy. Patients reported that the music
therapy was helpful in reducing anxiety, and it was therefore
decided to undertake some research in this area. To the author’s
knowledge, no clinical research has been published on music therapy
and motor neurone disease.
The aim of this
research project was to compare the effectiveness of a live music
therapy session, recorded music, and silence, in reducing anxiety
for patients with motor neurone disease. Twenty-one participants
with ALS/MND
receiving inpatient hospice services were recruited.
The study implemented
a repeated measures design, with participants acting as their own
controls. Participants experienced each of the three conditions
mentioned above, over a period of one week. A pre test-post test
design was used and participants completed the Hospital Anxiety and
Depression Scale (HADS) And Edmonton Symptom Assessment System (ESAS)
immediately before and after the intervention. Heart rate and
oxygen saturation levels were also measured pre and post.
Results of the study
were not significant in either the music therapy or recorded music
groups. The majority of participants (81%) reported little or no
anxiety prior to the interventions and therefore, little change was
noted in any of the groups. This was certainly in contrast to our
clinical work and suggests that more research investigating which
symptomatic issues are most prevalent in this population is
required.
Drs Qiao-Xin Li, Anthony White, Kevin Barnham, Paul Donnelly & Peter
Crouch
Department of Pathology,
The University of Melbourne
Zo-če MND Research
Grant
What is
the project?
Why are
we doing it?
Frustratingly, the MND community is all too aware that there are
very few therapeutics available to treat the disease, and that the
benefits of the therapeutics that are available are relatively
small. We believe the most significant obstacle in the development
of more effective therapeutics for MND is a fundamental lack of
knowledge in understanding what causes the disease and how currently
available therapeutics work. We are dedicated to this project
because we have a potential therapeutic for MND that is working in
mouse studies, and the expertise of our research team is in
developing therapeutics and defining how they work. Success in our
endeavours will establish the validity of our therapeutic for
potential use in humans and will provide valuable knowledge about
the causes of the disease.
What do
we hope to achieve?
By
achieving our aims, this study will help us understand how spinal
cord motor neurons die in MND. It will also help expedite the
development of effective MND therapeutics and/or confirm the
potential use of our compound CuATSM for use in humans.
What
does our work mean for people living with MND?
We
cannot promise that our work will lead directly to the use of CuATSM
as a more effective treatment for MND in humans. But we can promise
that every outcome from our project is a step closer to this
ultimate goal, and we desperately want this to give some hope to
people living with MND. Our research team is internationally
recognised as leading the world in the development of therapeutics
for neurodegenerative diseases such as MND. We want the MND
community to know we are committed to this project, and we hope this
brings them some assurance at times of immense personal hardship.
Where
to next?
Although we have some very promising results already, this is just a
first step towards defining the potential for CuATSM in treating
patients with MND. Defining optimal dose and treatment regimes in
the mouse model is our first priority. By achieving this we will
have the basis on which to best identify exactly how CuATSM prevents
the physical symptoms of MND. This
fundamental research will lead to a better understanding of the
pathological progression of MND and enable us to define whether our
CuATSM work can progress to humans, or whether chemists within our
team will be able to refine CuATSM to generate compounds with even
better therapeutic outcomes.
Professor Robert Rush &
Dr Mary-Louise Rogers
Human Physiology, School of Medicine, Flinders
University, SA
Motor neuron disease
(MND) is an illness of nerves resulting in a creeping paralysis and
death; there is no effective treatment. We have developed a genetic
therapy consisting of blood proteins capable of targeting specific
nerves chemically linked to a gene that can generate proteins and
other molecules, with the potential to benefit diseased motor
nerves. Our “immunogene” will deliver therapeutic genes to diseased
nerves in an MND mouse model, and we have thus far demonstrated
that the “immunogene” will work in the MND mouse. In addition we
have tested the “immunogene” product in cultured nerves and in a
small number of MND mice, to demonstrate the feasibility of
delivering genes that will turn off the mutant gene responsible for
motor neuron disease in the MND mouse. In collaboration with Dr
Rainer Haberberger, we have also shown that the “immunogene” can
deliver genes to sensory nerves in the healthy mouse, an important
observation that may allow the gene therapy to be used prior to the
onset of MND. This encouraging progress is enabling us to
confidently continue our project of delivering genes that will
modify the mutant protein responsible for motor neuron disease in
the MND mouse.
Postdoctoral Fellowships
Dr Anna King,
Menzies Research Institute,
University of Tasmania
Bill Gole Postdoctoral MND Research
Fellow 2008-2010
Investigating the causes and consequence
of axonal pathology in Amyotrophic Lateral Sclerosis
Motor neuron disease (MND) is caused
by a loss of function of the nerve cells controlling the muscles.
The nerve processes in ALS are frequently swollen with accumulations
of proteins and this may be responsible for their loss of function.
However the cause and consequence of these swellings is unclear. I
have developed a cell culture model that mimics these degenerative
changes in motor nerve cells, and have found that this pathological
feature is influenced by the health of the surrounding support
cells. I am using this model to investigate the factors and
mechanisms that cause motor neurons to degenerate, which may
indicate new therapeutic opportunities for an otherwise incurable
condition.
Dr Julia Morahan,
Department of Pathology,
University of Sydney
Bill Gole Postdoctoral MND Research
Fellow 2007-2008
Somatic mutations in motor neuron
disease?
Genetic
abnormalities
are
suspected to underlie sporadic, as well as familial, ALS. It has
recently been recognised that (1) genes may be “silenced” by
chemical changes (methylation) that are not picked up with the usual
genetic methods of analysis, and (2) duplication or deletion of
whole genes (increases or decreases in “copy number”) underlie much
of human variation and may be responsible for diseases such as ALS.
We investigated these types of changes in the brains of people with
ALS who had donated nervous tissue for research.
We found differences
in gene silencing in a number of genes that could play a part in ALS.
This work has opened a new avenue of research into ALS and it is
anticipated that other studies will follow this one.
In addition, a
preliminary study looking at duplication and deletion of genes in
the brains of people with ALS has shown some intriguing changes that
we plan to follow up in a larger study.
Dr Jennica Winhammar,
The prince of Wales Medical
Research Institute, NSW
Bill Gole Postdoctoral MND Research
Fellow 2008-2010
Clinical trial to assess the
neuroprotective properties of a sodium channel blocking agent in motor
neurone disease.
This project will
provide clinical trial information related to the potential
neuroprotective propertiesof a sodium channel blocking agent in
patients with motor neurone disease. Specifically, it will establish
whether this trial medication can slow disease progression. A
potential therapeutic response would provide impetus for a larger
scale, multi-centre clinical trial. In addition to providing
information about potential mechanisms of neurodegeneration and
their treatment, new quantifiable measures will be further developed
to objectively monitor MND patients in a clinical trials setting.
Victorian MND Research
Tissue Bank (2008)
This report outlines the outcomes of the
Motor Neurone Disease Research Tissue Bank of Victoria (mndRTBv) as
a result of the support from MWD Research lnstitute of Australia (WINDRIA).
Summary report of the mndRTBv activities
for communication to the MND Community.
The mndRTBv was established in 2003 as a
repository of fluids {blood and cerebrospinal fluid (CSF)) and
brains and spinal cords obtained from people diagnosed with Motor
Neurone Disease (WIND). From these samples, the neuropathologist is
able to confirm diagnosis of the illness. More importantly, these
samples are used for research purposes which may lead to
improvements in diagnosis, the development of early diagnostic
tests, therapeutic interventions and the development of preventative
strategies.
The bank has a total of 27 MND brain and
spinal cord donations, 4 control 'normal' brain and spinal cord
donations as well as a number of cerebrospinal fluid and blood
donations. Tissue has been provided to 13 new and continuing
research projects with research being conducted by research groups
at The University of Melbourne, Howard Florey lnstitute and The
University of Sydney. In the past 12 months this research has
resulted in 10 Australian and international scientific publications
and presentations.
The funds received from the MNDRIA have
assisted the mndRTBv to maintain and expand the collection and with
associated tissue processing costs.
The mndRTBv would like to acknowledge
the generosity shown by the donor and donor families in donating
tissue to the mndRTBv. It is an act of great foresight and kindness
to give at a time of loss, so that others may be helped in the
future.
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