INTERNATIONAL
FRDA CONFERENCE
HELD
IN ADELAIDE, ON 30 AUGUST 1998
A
one day meeting concerning advances in research in
Friedreich Ataxia was held on the 30th August in Adelaide.
This meeting brought together people working in the field of
Friedreich Ataxia from a number of countries as well as the
related fields of iron metabolism and triplet repeat
diseases. Some of the information presented has not been
accepted for publication in the scientific literature and
therefore will not be detailed in this report. This meeting
highlighted not only the cooperatively of the Australian
researchers but that this also occurs in the international
arena. Through informal discussions and meetings over the
past year or so, a concerted effort has been made not to
waste resources duplicating research efforts apart from
areas where it is essential to confirm exciting findings.
This has ensured that we have made the best progress
possible and as you will see from the meeting report we aim
to continue in this collaborative cooperative
manner.
A
bit of background first. Friedreich ataxia is due to faults
in the gene known as FRDA, which produces the protein
frataxin. Most of the genetic alterations are an expansion
of a GAA repeat (three letters of the genetic code) in
intron 1 of this gene but point mutations have also been
found in some patients where a single letter of the genetic
code for frataxin is altered. Last year it was found that if
the yeast equivalent of frataxin is knocked out in the
yeast, iron accumulates in the mitochondria. Mitochondria
are the energy sources for cells. Other evidence for the
involvement of mitochondrial iron include the abnormalities
in enzymes from the mitochondria in heart muscle from people
with Friedreich ataxia as well as the finding of iron
deposits in heart muscle. These tissues are known to be
affected in patients with FRDA but are not readily
accessible from patients to check the effect of
therapies.
The
first presentation was from Professor Massimo Pandolfo from
Montreal who laid the foundation for the rest of the
meeting. He elegantly summarised the current status of
research findings and highlighted areas where further work
was required to confirm preliminary results. A particular
focus was a discussion about the evidence for mitchondrial
iron build up underlying Friedreich ataxia. His laboratory
found clearly increased levels of iron in the mitochondria
of heart muscle from one person with FRDA but not in
fibroblasts (skin cells).
Dr
Martin Delatycki (Melbourne) spoke about his findings
looking at fibroblasts, which are skin cells from people
with Friedreich ataxia. He did find a small but significant
difference in iron levels in mitochondria from people with
FRDA compared to controls. These experiments have been
performed in order to determine if there is a readily
accessible tissue that shows a biochemical phenotype. Then
it may be possible to both test the effects of therapeutic
measures and monitor it during a trial.
Mouse
models for human diseases offer the opportunity to examine
the way that the gene fault causes the disease. Once it has
been confirmed that the mouse has a similar clinical picture
to humans, then the mouse can be used to test possible
therapeutic interventions. Dr Michel Koenig from Strasbourg
in France who along with Professor Pandolfo found the gene
which is faulty in Friedreich ataxia, talked about a mouse
model for Friedreich ataxia that they are generating where
the gene is disrupted. The first litter has only just been
born and is currently being investigated.
Other
forms of mouse models are being generated in the Melbourne
and Montreal labs. Professor Pandolfo is looking at making a
mouse that has the expanded GAA repeat in the gene. Dr. Kate
Elliott (Melbourne) spoke of the mouse being developed there
which will have the G130V point mutation. These mice have
not been produced yet and discussion centred around how the
presence of these gene faults would affect the
mice.
Dr.
Koenig then spoke about his work in looking at proteins
which interact with frataxin which may then give a better
understanding of how the deficiency of frataxin leads to
Friedreich ataxia. The interacting protein he found,
mitochondrial processing peptidase b, causes maturation of
frataxin into its fully functional form. This unfortunately
does not shed further light into how frataxin functions.
Work to find further partners is continuing in both the
Montreal and Strasbourg laboratories.
Another
avenue for investigation of frataxin function was suggested
by Dr Des Richardson from the University of Queensland. In
order to understand the role of frataxin in mitochondrial
iron overload, knowledge of the iron metabolism of the
mitochondrion is crucial. He presented some of his finding
in examining how iron gets to the mitochondria in red blood
cell precursors which might provide clues that may be
important in understanding the role of frataxin in other
cells.
Phillipa
Lamont, a neurologist from Perth, talked about possible
therapies based on the current understanding of the
underlying problem in Friedreich ataxia. It is believed that
the build up of iron in mitochondria leads to the production
of free radicals which damage the cells. Therefore,
potential therapeutic options include drugs to remove iron
from the mitochondria (iron chelation) or drugs to mop up
the free radicals produced (antioxidants). There are many
different antioxidants including co enzyme Q10 which may
have a role in the treatment of Friedreich
ataxia.
The
only approved drug which removes iron from cells is the iron
chelator, desferrioxamine. This has been used extensively in
iron overload conditions such as thalassaemia. It is unclear
whether this drug removes iron from the mitochondria. It was
universally agreed at the meeting that it was not
appropriate to use this drug to treat Friedreich ataxia
because it removes iron from cells so effectively causing
depletion of iron from where it is required within the
cell.
Erica
Becker who is a PhD student with Des Richardson in
Queensland discussed various new iron chelators which have
the potential to be used in Friedreich ataxia. She
demonstrated that some of these can be used to remove iron
from mitochondria although they also removed iron from
cells. It needs to be emphasised that these chemicals are
very much at an early laboratory research level.
Professor
Bob Williamson, the Director of the Murdoch Institute
discussed gene therapy and possible ways that this may be
used in the future for treating Friedreich ataxia. He then
summed up the meeting and put into context just how far
research into Friedreich ataxia had come in the two years
since the gene responsible for the condition was
discovered.
Samantha
Dixon from NSW spoke on behalf of the support groups who met
at the same time as the scientific meeting. She raised the
issue of availability of educational material for families,
their support network including families and clinicians. The
overriding concern was the desire to have treatment trials
set up in Australia. She asked whether potential therapies
could be combined
The
ensuing discussion began with Dr Garth Nicholson, a
neurologist from NSW, pointing out the importance of doing
such trials in a proper manner which requires significant
funding. The issue of how to monitor the benefit or
otherwise of medications in the trial was also discussed. If
a drug slows the progression of Friedreich ataxia this may
be very difficult to detect by the usual clinical methods.
Therefore, important areas of research include those which
look for methods of detecting benefits from drugs in a more
subtle fashion that is currently available. Information from
a London group involved in the use of specialised technique
called magnetic resonance spectroscopy presented at the
neuromuscular meeting which followed on from the Friedreich
ataxia meeting may prove to be useful in this respect.
Professor Pandolfo pointed out the possible use of
biochemical markers such as erythrocytic protoporphirin IX,
which is above normal in all FA patients, and possibly
plasma malonaldheyde (no data yet) for monitoring the
response to various therapies.
The
meeting from a scientific perspective was very successful in
that it allowed open discussion regarding research results
and a clearer picture regarding the cause and possible
therapies for Friedreich ataxia was presented.
The
organisers of the meeting would like to again thank those
who helped financially with the meeting including the
Theresa Byrne Foundation and the Friedreich Ataxia
Associations of Victoria and NSW.
MARTIN
DELATYCKI SUE FORREST
Medical
Geneticist Head Scientist, Gene Discovery
INTERNATIONAL
FRIEDREICH'S ATAXIA CONFERENCE
HELD
IN ADELAIDE, AUSTRALIA, ON 30 AUGUST 1998
SUMMARY
OF PROCEEDINGS
This
summary is provided through the co-operation of The Murdoch
Institute, Melbourne, Australia and contributors to the
proceedings of the Conference. It represents a lay person's
analysis of the main points and is presented with a view to
providing an overview of the current state of research into
Friedreich's Ataxia.
The
Program:
The
Frataxin Story
Dr
Massimo Pandolfo
Understanding
Frataxin Gene Function and Mutation Analysis
Dr
Michel Koenig
Dr Sue Forrest
Dr Martin Delatycki
Dr Kate Elliott
Iron
Dr
Des Richardson
Dr Michael Koenig
Dr Martin Delatycki
Therapeutic
Strategies
Dr
Phillipa Lamont
Ms Erika Becker
Professor Bob Williamson
Dr
Pandolfo's presentation set the scene for much of the
subsequent discussion and the later presentations. It would
appear from yeast studies that there is an excess of iron in
the mitochondria, that is, within the structures containing
respiratory enzymes and which are responsible for producing
energy. In the yeast model, developed by Kaplan and his
associates, lack of expression of the gene results in an
excess of iron in the mitochondria. One salient issue is
whether frataxin acts as an exporter of iron from the
mitochondria. It is believed that excess free iron in the
mitochondria generates highly toxic free
radicals.
In
the human, frataxin is a mitochondrial protein which has no
direct interaction with the membrane.. Vulnerable cells
require a high level of frataxin and Friedreich's patients
exhibit a profound deficiency of frataxin in these.
Conversely, there does not seem to be a change in the
fibroblasts, which are cells obtained from a skin biopsy, or
iron-related aspects in fibroblasts amongst
patients.
There
is deficiency of iron-sulphur enzymes in the heart but not
in skeletal muscles or fibroblasts. This appears to be due
to the sensitivity of these enzymes to free radicals.
Mitochondrial DNA is not depleted in the heart, spinal cord,
brain or muscle of patients.
One
might conclude that Friedreich's Ataxia results in a
frataxin deficiency leading to an increase in mitochondrial
iron and free radicals. This results in cell damage and cell
death in specific tissues such as dorsal root ganglia
resulting in that person having Friedreich's
ataxia.
Dr
Koenig stated that FA is a Caucasian disease and that there
is a correlation between expansion size and severity of the
illness. There also appears to be a correlation between age
of onset of FA and the size of the expansion. FA is caused
by a reduction of frataxin, not a complete obliteration of
it. This has important and positive implications for future
treatment. Dr Koenig is currently finalising work on a
knockout mouse model.
The
Murdoch group provided interesting insights into the
relationship between point mutations and severity of
illness. While FA normally results from an atypical
expansion of the GAA repeat on both alleles, between one and
five per cent of cases are caused by a single nucleotide
change in the gene. Some point mutations result in severe
Friedreich's ataxia whist others cause milder FA. This gives
insight into which parts of frataxin are important for
function. Of interest here was Koenig's presentation of a
variety of FA patients with lengthy repeats on two alleles,
but whose physical characteristics appeared relatively
normal.
The
Murdoch group is currently involved in developing a mouse
model that imitates a milder form of FA.
Research
at the University of Queensland's Department of Medicine
could have significant implications for FA. Papers presented
by Dr Des Richardson and Ms Erika Becker provided insights
into the nature of mitochondrial iron transport and iron
overload, as well as the development of new iron
chelators.
In
previous research Richardson demonstrated that haem
synthesis in the mitochondrion was inhibited through the
intervention of a specific inhibitor (succinylacetone)
resulting in an iron accumulation because iron continued to
be transported into the mitochondrian despite the lack of a
facility for binding it. When the binding facility is added,
or when the inhibitor is removed, iron is incorporated to
form haem which is transported out of the
mitochondrion.
Richardson
believes that iron accumulation in the mitochondrion in FA
patients could be the result of a defect in mitochondrial
iron release. He postulates that since frataxin could be
involved in regulating iron uptake by the mitochondrion it
becomes necessary to investigate the pathway of iron uptake
from the endosome to the mitochondrion.
Ms
Becker pointed out the problems attaching to iron chelators,
particularly given their serious side effects and the
unavailability of orally administered chelators. She
referred to the capacity of arolhydrazone chelators to
remove iron from iron-loaded mitochondria in erythroid
cells.
Becker's
current research attempts to identify chelators that are
more efficient than desferrioxamine. She has identified
three as having greater activity than desferrioxamine and
intends examining the usefulness of these in removing iron
from mitochondria. It is very important to realise that this
work is in the very early laboratory research stage and is
not immediately applicable to therapy for FA.
Dr
Phillipa Lamont from Royal Perth Hospital in Western
Australia presented an overview of potential therapies for
FA. She referred to the problems associated with the
currently available iron chelators, indicating that these
may not remove iron from the mitochondrion although they are
effective in depleting iron from cells in general. Any
depletion of such cytosolic iron could well lead to iron
deficiency.
The
Lamont paper suggested that antioxidants aimed at reducing
free radicals in cells provided a safer and more beneficial
effect than the present chelation therapy.
Professor
Bob Williamson, Director of the Murdoch Institute, presented
an overview of the present state of the art in gene therapy
as it relates to FA. Work on mouse models is proceeding
apace and, while gene therapy is still not available to FA
patients, more is being found out about its possibilities.
FA is regarded as a good candidate for gene therapy and
research on adeno associated viruses as a delivery system is
moving ahead quickly.
The
possibility of early trials with accepted antioxidants
should be considered now. It is imperative that these be
conducted under controlled conditions. While sufferers and
carers are understandably frustrated at the delay in
determining a treatment, it should be realised that great
advances have been made in the two brief years since the
discovery of the FA gene. It is also encouraging that there
are now clinicians with an understanding of FA and its
effects in every Australian state. Moreover, the study of FA
amongst researchers has increased dramatically
worldwide.
Peter
Rousch
Wollongong
Australia
September 1998
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