biochemical mechanisms in friedreich ataxia robert b. wilson, m.d., ph.d. friedreich’s ataxia...

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

GAAGAAGAAGAAGAAGAAGAAGAAGAAGAA

GAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAA




GAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAAGAA











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

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)

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

biochemical mechanisms in friedreich ataxia robert b. wilson, m.d., ph.d. friedreich’s ataxia...

Documents

frda fe frataxin ee

oxidants fe s s ee

energy slide

clinical trials

bases slide

translation protein

fes ros fe

frda gene normal