Australian Life Scientist
Biotech News

Excess iron and Friedreich's ataxia

While Friedreich's ataxia is a rare disorder, tracking down the role of the
protein implicated in the disease has opened up new therapeutic potentials.
Graeme O'Neill 28/08/2008 13:40:00
Friedreich's ataxia is a crippling neurological disorder that affects about 1
in 30,000 individuals, making it the most common of the inherited gait
disorders, or ataxias.

While there would be fewer than 130 patients in the greater metropolitan
Melbourne area, population 3.85 million, by the peculiar calculus applying to
autosomal recessive disorders, there would be around a dozen carriers on every
crowded commuter train entering Melbourne's City Loop during the morning rush.
The mutant allele's frequency in Western populations is around 1 in 90.

Associate Professor Martin Delatycki has seen more than 100 Friedreich's
patients during his monthly clinics at Monash Medical Centre – at his most
recent clinic, only one patient was from Victoria; the rest from interstate and

Delatycki is a clinical geneticist director of the Bruce Lefroy Centre for
Genetic Health at Melbourne's Murdoch Childrens Research Institute, and
specialises in diagnosing and treating the disorder.

The first symptoms of Friedreich’s ataxia typically manifest in childhood,
between the ages of five and 15. Patients develop progressive weakening of the
muscles of the arms and legs, lose coordination and develop an unsteady gait.
Curvature of the spine, and deformed feet, eventually force them into a
wheelchair. Hearing and vision may deteriorate, speech becomes slurred, and they
develop cardiomyopathy and an irregular heartbeat.

Diagnosis is straightforward enough, but until recently there was no effective
treatment for patients with the progressive, invariably fatal disorder.

Today, however, there is light on the therapeutic horizon – actually, three
lights. Delatycki says three drugs are in clinical trials overseas which
approach the underlying metabolic defect in Friedreich’s ataxia from different
and potentially complementary directions.

Delatycki described his research at the annual scientific meeting of the Human
Genetics Society of Australia in Adelaide recently.

---PB--- Genetics of Freidreich’s

The Murdoch Institute is one of the world’s leading centres for Friedreich’s
ataxia research, thanks to former director Professor Bob Williamson’s central
role in tracking down and identifying the mutant gene.

Williamson pinpointed the location of the gene via linkage disequilibrium –
the tendency of chromosome segments to carry highly conserved combinations of
alleles of adjacent genes to be transmitted intact between generations, along
with unique DNA markers that distinguish between mutant and normal haplotypes.

In 1988, Williamson and his colleagues tracked the defect to the 9q13-q21
region, on the long arm of chromosome 9. The mutation involved a gene called
FXN, coding for a novel protein frataxin.

In all but a few patients, the mutation involves the expansion of a repeated GAA
trinucleotide in the gene’s first intron, so the protein itself is unaltered.

Most trinucleotide repeat expansion disorders, including Fragile X syndrome,
Huntington’s disease and spinobulbar muscular atrophy, introduce a
variable-length sequence of a particular amino acid within the protein itself,
turning it toxic.

Although encoded by a nuclear gene, the protein is exported to mitochondria.
Insufficiency in Friedrich’s patients appears to result in progressive buildup
of unbound iron.

The highly reactive iron atoms spawn oxidising free radicals that eventually
destroy frataxin-deficient mitochondria in the patient’s neurons. As affected
neurons and peripheral nerves die off, patients progressively lose coordination
and develop sensory impairments.

Delatycki says it’s still not clear how frataxin helps maintain iron
concentrations within safe bounds in mitochondria, but once the fundamental
problem was traced to a toxic excess of iron, multiple therapeutic avenues
opened up.

Researchers reasoned that antioxidants could reduce the damage to mitochondria.
Drugs to ramp up frataxin synthesis, or chelating agents to remove excess iron
from mitochondria, might also be effective.

---PB--- Clinical trials

Overseas, Idebenone, a powerful antioxidant that penetrates the blood-brain
barrier, is in Phase 3 trials. Researchers including Delatycki and his team are
also trialling an iron chelator, Defereprone.

Cell studies and an open label study in 11 individuals with Friedreich’s
ataxia indicated that erythropoietin, which boosts production of red blood
cells, also had potential. Delatycki is working with a US group to conduct a
Phase II/III placebo-controlled study.

Extra red blood cells require increased synthesis of iron-rich haemoglobin, and
excess iron may be excreted during their rapid turnover.

Delatycki’s research group at the Murdoch Institute is conducting laboratory
studies of compounds that could remedy the problem at source, by increasing
fretaxin synthesis.

The laboratory team, led by Dr Joe Sarsero, is developing a knock-in transgenic
mouse model of the disorder, by introducing the human form of the gene with the
trinucleotide expansion repeat mutation – they have already confirmed that the
normal human gene is a perfectly adequate substitute for the murine frataxin

“We’re also trying to establish clinically useful measures of changes in
human patients as the disorder progresses – how it affects walking, hand
movement, vision and eye movement, hearing, and general quality of life,”
Delatycki says.

“This is a very slow, progressive disorder. Motor neuron disease typically
takes two years to develop, but Friedreich’s takes 30 to 40 years, and the
individual rate of progression is highly variable.”

These clinical measures are essential for assessing how individuals are
responding to experimental drugs. “We’d love any drug that could reverse the
symptoms, but if it could just slow its progression by 10, 20 or 30 per cent …
Given the long course of the disease, any increase in the lifespan, and the
quality of life, would be very significant.”

As a recessive disorder, Friedrich’s ataxia occurs only when both parents
carry the mutation, and then only in one in four of their offspring, on average.

Delatycki says an unusual aspect of this pattern of inheritance is that the age
of onset, and the severity of the disease, is determined by the allele with the
fewest trinucleotide repeats – the mechanism involved is unclear, but one
hypothesis is that the expansion creates a defect in chromatin structure that
limits the access of the cell’s transcription machinery to the frataxin
gene’s promoter.

In Huntington’s and several other trinucleotide repeat expansion disorders,
the longer allele usually determines the age of onset and severity, so the
disorders exhibit a dominant pattern of inheritance.

The recessive pattern of inheritance, and the early age of onset, also means the
disorder rarely affect more than one generation of a family. Despite the
disease’s rarity, Delatycki says its nature has attracted a diverse range of
specialists from other fields, including mitochondria and iron-metabolism

“There has been a huge increase in interest in Friedreich’s ataxia since the
gene was identified, and we discovered why nerve cells die. We think the
frataxin protein’s main role in mitochondria is in the production of
iron-sulfur clusters that are essential for energy production.

“When frataxin levels are insufficient, there is a buildup of free iron in the
mitochondria, creating oxygen free radicals that damage multiple mitochondrial
respiratory chain enzymes.”

He says the Friedreich’s Ataxia Research Association (Australasia) is
“incredibly active” in raising funds for research.

“They’ve funded our program for many years now, and they also play a support
role for people newly diagnosed with the disorder.”

Friedreich's Ataxia Research Alliance (FARA)
P. O. Box 1537 Springfield, VA 22151
Tel               (703) 426-1576       ;

FA Patient Registry:
E-Bulletin Sign-up:


The legacy of Marie Schlau: literature to help cure Friedreich's Ataxia

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Research projects currently being financed by BabelFAmily

Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:

1) Gene Therapy for Friedreich's Ataxia research project:

The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.

2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.

The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.



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