Friedreich Ataxia Research and Prospects for Friedreich Ataxia Research and Prospects for Therapy...

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  • Friedreich Ataxia Research

    and Prospects for Therapy

    Grazia Isaya, MD, PhD

    NAF 53rd Annual Meeting Chicago 2010

  • Outline

    •Friedreich Ataxia (FA)

    •Frataxin

    •Frataxin and Iron-Sulfur Cluster Synthesis

    •FA Pathophysiology

    •Emerging Treatments for FA

  • ιAutosomal recessive (~1:40,000) ιProgressive ataxia ιHypertrophic cardiomyopathy (60%) ιDiabetes mellitus (30%) ιMuscle weakness, scoliosis

    Friedreich Ataxia (FRDA)

  • Friedreich Ataxia: Molecular Basis Campuzano et al. 1996

    FRDA Frataxin (210 aa)

    Inhibition of mRNA synthesis

    Frataxin depletion(GAA)n>60

    •How is frataxin normally made? •What does frataxin normally do? •What happens when there is not enough frataxin? •What can be done to ameliorate the disease?

  • Mitochondrial Matrix

    Cytoplasm

    frataxinleader

    MPP

    Synthesis of Frataxin

    Protein Import

    frataxin

    Nucleus

    mRNA

    Precursor Function

    Processing

    (GAA)n 1

    2 3

    4

    5 Fe

  • •What exactly is mitochondrial iron

    metabolism?

    •And how does Frataxin relate to this process?

  • Mitochondrial Iron Metabolism

    ATP

    mtDNA

    OXPHOS mtDNA

    •DNA synthesis •DNA repair •Protein synthesis •O2 Transport •Drug metabolism •Oxidant defense •…

    heme Fe-S

    Fe2+

    OH Fe2+H2O2

    O2-

  • Frataxin

    Fe2+ ↓

    Fe3+ Fe2+

    Fe(O,OH)6

    Heme

    Aco

    3Fe-4S Aco

    4Fe-4S

    ISU ISU 2Fe-2S

    Ferro- chelatase

  • Johnson et al. Annu Rev Biochem 2005

    Biological Fe-S Clusters

  • Fe-S Cluster Synthesis in Prokaryotes

    Marc Fontecave & Sandrine Ollagnier-de-Choudens Arch Biochem Biophys 2008

  • Fe-S Cluster Synthesis in Eukaryotes

    Tracey A. Rouault & Wing Hang Tong TRENDS in Genetics 2008

    /Nuclear

  • Tracey A. Rouault & Wing Hang Tong TRENDS in Genetics 2008

    Fe-S Cluster-Containing Enzymes

  • Aerobic Avg of 2 exp for (HFxn42)n and 3 exp for HFxn 81

    Time (min)

    50 100 150 200

    A 426

    0.05

    0.10

    0.15

    0.20

    0.25

    0.30

    NFS1/ISD11+ ISCU (HFxn42)n+ NFS1/ISD11+ ISCU

    Frataxin promotes [2Fe-2S] Assembly on ISCUFrataxin promotes [2Fe-2S] Assembly on ISCU

    NFS1 ISD11

    + + L-CysISCU

    + Human Frataxin + Iron

    + Iron

  • FXN Isd11

    Nfs1 Isu1Fe

    2. ↓ Mitochondrial Fe-S Enzymes

    mtDNA

    5. ↓ ATP

    Nuclear Genome

    1. Frataxin (FXN) Deficiency

    Mitochondrial Matrix

    3. ↑ Free Cys Cystine

    ↑ Fe3+ ↑ Fe2+ H2O2

    ↑ OH•

    Cys

    OH 4. mtDNA Instability

    6. ↓ Cellular Fe-S Enzymes

    7. Nuclear Genome

    Instability

  • •Frataxin deficiency causes progressive accumulation of cellular damage.

    •How can we stop this?

  • Fe-S

    ROS Fe

    Therapeutic Targets in FA

    Idebenone (Phase III) A0001 (Phase I) Other antioxidants (Pre-

    clinical)

    Deferiprone (Phase II) Additional Iron Chelators (Pre-clinical)

    Frataxin

    HDACi (Pre-clinical) EPO (Early clinical) Protein replacement

    (Pre-clinical)

    Courtesy of R. Wilson

  • Other Approaches

    •iPS Technology

    •Gene Therapy

  • •Disease mechanisms •Drug screenings •Effects of new drugs •Cell therapy

    The promise of human induced pluripotent stem cells for research and therapy.

    Nishikawa S, Goldstein RA, Nierras CR.

  • Cell Death

    Frataxin Deficiency

    •DRG Neurons •Cardiomyocytes •Pancreas β Cells

    •Other Cells

    No obvious negative effects

    FA iPS

  • FA results from low levels of the mitochondrial protein frataxin.

    Frataxin plays an essential role in iron metabolism and in the protection from oxidative stress.

    Emerging therapies target the negative effects of frataxin deficiency (e.g. ROS, toxic iron); they also target frataxin expression (e.g. HDAC inhibitors).

    iPS technology for FA is also actively pursued in the research pipeline.

    Conclusions