|
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.
|