Biochemical Mechanisms in Friedreich Ataxia
Robert B. Wilson, M.D., Ph.D.
Friedreich’s Ataxia Symposium
14 November 2009
Potential Conflicts of Interest
Penwest
Apopharma
DNA is a Double Helix Comprising Four Bases
DNA is Packaged by Histone Proteins
DNA Encodes Proteins by Transcription and Translation
Protein
The FRDA GeneNormal: <40 GAA repeats
Friedreich’s ataxia: ~100 to >1700 GAA repeats
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DNA Encodes Proteins by Transcription and Translation
Protein
From Pandolfo, Archives of Neurology, 2008
GAA Repeat Expansions in the FXN GeneMay Silence the Gene by Multiple Mechanisms
The FRDA Gene Encodes Frataxin
Normal FRDA Gene
(GAA)<40 Energy
Mitochondrion
The FRDA Gene Encodes Frataxin
Normal FRDA Gene
(GAA)<40 Energy
Mitochondrion
GAA Repeat Expansions Decrease Frataxin Expression
Energy
Mitochondrion
Oxidants
FRDA Gene with Expansion
(GAA)>100
Iron-Sulfur Cluster Assembly Simplified
Fe
Fe
Fe
Fe
S
S
S
SFeFrataxin
e-
e-Energy
Iron-Sulfur Cluster Assembly in FRDA
FeFrataxin
e-e-Oxidants
FeFe
S
S
Fe
Fe
Fe
Fe
Fe
e-
e-Energy
Fe-S
ROS Fe
Underlying Vicious Cycle in FA
Idebenone (Phase III trial)MitoQ (Early clinical)A0001 (Pre-clinical)
Deferiprone (Phase II trial)Additional Iron Chelators
(Pre-clinical)
Frataxin
HDACi (Pre-clinical)EPO (Early clinical)Protein replacement
(Pre-clinical)
Fe-S
ROS Fe
Underlying Vicious Cycle in FA
Idebenone (Phase III trial)MitoQ (Early clinical)A0001 (Pre-clinical)
Deferiprone (Phase II trial)Additional Iron Chelators
(Pre-clinical)
Frataxin
HDACi (Pre-clinical)EPO (Early clinical)Protein replacement
(Pre-clinical)
Research(Finding Potential Therapies/Drugs)
Pre-Clinical(Testing in Laboratory)
Phase I(Human Safety
Trial)
Phase II(Human Safety
and Efficacy Trial)
Phase III(Definitive Trial)
Available to Patients
Decrease Oxidative Stress
and/or Increase Mitochondrial
Function
DecreaseIron
Toxicity & Increase
Fe-S clusters
IncreaseFrataxin or FA gene
Expression
Gene Therapy
FrataxinProtein-
Replacement
High-Throughput Screening for New
Drug Discovery
Ideb
eno
ne
HD
AC
- L
ead
ing
HD
AC
s -
New
Iro
n C
hel
ato
r –
Def
erip
ron
e
Fe-
S c
lust
ers
HS
V-1
FR
DA
TA
T F
rata
xin
EP
O &
EP
O m
imet
ics
San
ther
a
Pen
wes
t
Apo
Pha
rma
Mit
och
on
dri
al F
un
ctio
n
Fra
taxi
n
FR
DA
Gen
eT
ran
scri
pti
on
NIH
/Har
vard
Rep
ligen
Scr
ipps
Ins
titut
e, L
a Jo
lla,
CA
Uni
vers
ity o
f M
adrid
an
d U
nive
rsity
of
Oxf
ord
Wel
ls C
ente
r fo
r P
edia
tric
Res
earc
h, I
ndia
napo
lis,
IN
Uni
vers
ity o
f P
enns
ylva
nia
&U
nive
rsity
of
Cal
iforn
ia,
Dav
is
May
o C
linic
, R
oche
ster
, M
N
MD
And
erso
n, H
oust
on,
TX
&
M
urdo
ch C
hild
ren’
s R
esea
rch
Inst
itute
, A
ustr
alia
Pio
gli
tazo
ne
INS
ER
M -
Hôp
ital R
ober
t D
ebré
FARA has supported, and is supporting, these efforts by providing various combinations of direct funding, essential clinical infrastructure, advocacy and awareness efforts.
7 Clinical Trials 8 Approaches
A00
01
FA Treatment Pipeline - 2009
Mt
Gen
e T
her
apy
Uni
vers
ity o
f M
inne
sota
and
May
o C
linic
Var
enic
lin
e /
Ch
anti
xU
nive
rsity
of
Sou
th F
lorid
aA
nd C
hild
ren’
s H
ospi
tal o
f P
hila
Neuro- Transmission
Modifying Therapy
Uni
vers
ity o
f P
enns
ylva
nia
S
mal
l R
NA
s
Neuro-protection
EG
b76
1IP
SE
N
MU
V,
Aus
tria
& O
ther
gro
ups
Mul
tiple
Gro
ups
Lund
beck
Acknowledgements
David Lynch, M.D., Ph.D.Ron Bartek
Jennifer Farmer, M.S.Felicia DeRosa
Friedreich’s Ataxia Research Alliance
William Hartnett, Marianne Wilcox, Martin Ohman
and the rest of the EDS team
Our patients and their families
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