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FRDA 1999-Friedreich's Ataxia Research Conference


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FRDA 1999-Friedreich's Ataxia Research Conference

April 30-May 2, 1999
Bethesda, Maryland
Cosponsored by: FARA (Friedreich's Ataxia Research Alliance) & the National Institutes of Health

Conference Summary

On April 30-Mary 2, 1999, the National Institutes of Health (NIH) and FARA cosponsored a workshop on Friedreich's ataxia and the related sporadic ataxias. The workshop brought together eighty of the world's leading scientists with insights to contribute to the search for treatments and cures for Friedreich's ataxia (FRDA) and the related sporadic ataxias.

NINDS Director, Dr. Gerald Fischbach, gave the opening address and set expectations very high by saying, "I don't think there is any disorder more primed for fundamental advances than Friedreich's ataxia ... it really is at the crossroads right now of the very best, and most modern in genetics and mitochondrial disorders and in understanding the cell biology of neural degeneration." That sense of real expectation and promise carried through the eight sessions and three days of discussion, as these scientists shared their insights and findings and began to test new hypotheses against the experience of their peers. It was clear that a great deal of progress had been made since identifying the FRDA disease gene and that several promising avenues of approach were emerging.

FARA Board Member Dr. Rob Wilson of the University of Pennsylvania Medical Center, served as the Principal Investigator. He prepared the application for the NIH grant that funded the workshop, and led the effort to craft the agenda and select participants. Dr. Wilson established a scientific organizing committee including the other two scientific members of FARA's Board of Directors, Dr. Massimo Pandolfo of the University of Montreal and Dr. Bronya Keats of the Louisiana State University Health Sciences Center. Additional members of the scientific organizing committee were Dr. Michel Koenig of the French Institut Genetique and Dr. Kenneth Fischbeck of the NIH National Institute of Neurological Disorders and Stroke (NINDS).

The progress made in understanding the fundamental mechanism of FRDA was immediately obvious. Knowing which gene is responsible for the disorder had enabled investigators to determine the following:

  • Frataxin is the protein the FRDA gene (X25) expresses.
  • Frataxin regulates iron levels in the mitochondria of some cells, and excessive iron in the mitochondria results in damage from reactive oxygen species (free oxygen radicals) and low energy production.
  • The tri-nucleotide repeats cause the formation of what is being called "triplex" or "sticky" DNA along the double helix.
  • "Sticky DNA" hampers the genetic transcriber from breaking through and reading the Frataxin gene's code.
  • With reduced transcription, there is less RNA to go out and collect the amino acids required to form the Frataxin protein;
  • Therefore, there is insufficient Frataxin protein to regulate iron metabolism within, and iron export from, the mitochondria.

 Discussion Points
During the course of the workshop, four promising avenues emerged as calling for the most immediate attention - antioxidation, iron chelation, breaking down the "sticky DNA", and developing animal models.


  •  Antioxidants. One approach to reducing the impact of FRDA is to attempt to bind up as many reactive oxygen species as possible, especially where they are causing most damage. In the final session of the workshop, a French team led by Doctors Rustin, Rotig and Munnich briefed the workshop participants on preliminary results of a clinical trial in which the antioxidant, Idebenone, is being administered orally to FRDA patients in France. These preliminary results center on the observation that in most of the patients in the trial, the heart's left ventricle hypertrophy was reduced by roughly 20-30 percent over a 4-9 month period. There have been anecdotal indications, too, that some of these patients are enjoying some improvement in fine motor skills. No harmful side effects have yet been detected. The Idebenone trial continues in France.

    Preparations are underway in the United States to conduct an Idebenone clinical trial with FRDA patients. A high quality U.S. trial is especially important because the Federal Drug Administration (FDA) has not yet approved Idebenone for use with FRDA patients. An effective trial could lead to FDA approval and render Idebenone eligible for health insurance coverage. FARA is working closely with NIH, the scientific members of FARA's Board, and other interested scientists to help facilitate rapid development of the most effective protocols and approaches for such a trial. Many difficult questions must be answered [e.g., How many patients and with which genotypes and phenotypes? How many centers? What uniform scales for measuring progress will be used? Can testing for Phase 1 (safety), Phase 2 (efficacy) and Phase 3 (dosage) be conducted in the same clinical trial?]

    In addition to FARA's role in this preparatory phase, FARA plans to assist in the trial by helping identify and assemble the patient participants; by providing communication links between the scientific community (NIH and the trial centers) and patient community; and, when appropriate, by interfacing with the pharmaceutical industry. If you or a member of your family diagnosed with FRDA would consider participating in this or any other future FRDA trial, please complete and mail the patient data base form found in this FARA Update.
  •  Sticky DNA. FRDA's lengthy tri-nucleotide (GAA) repeats appear to cause one side of the double helix to fold back onto itself and form the bonds of a structure being called "sticky DNA". This greatly diminishes the genetic transcriber's ability to get past the repeated sequences to read the genetic code. If the transcriber cannot read the code and pass it to the RNA, the Frataxin protein cannot be formed. Workshop participants discussed the prospects for finding a pharmacological approach to breaking down the 'sticky DNA' so the transcriber could proceed normally past the repeats and read the gene's code. Several of the participants undertook to collaborate on this approach and are working now to develop the technical approach necessary to conduct laboratory tests on a large number of compounds for effectiveness in breaking down the sticky DNA.
  •  Iron Chelation. Knowing that the shortage of Frataxin protein leads to excessive levels of iron in the mitochondria, scientists are experimenting with techniques for reducing those iron levels by binding and drawing it out (chelating). A team from the University of Utah, led by Dr. Jerry Kaplan, briefed the workshop on the clinical trial it has begun with FRDA adult patients over the age of 18 to test chelation therapy using desferrioxamine. This NIH-sponsored trial is scheduled to run for one year, after which affected tissue from the patients will be tested to see if iron overloads have been reduced. Scientists elsewhere are experimenting with other iron chelators such as the orally administered compound, L1. It seems probable at this point that, if iron chelation is to prove effective as a treatment of FRDA, the chelating compounds used will have to be effective in reducing iron levels selectively in the mitochondria as opposed to elsewhere in the cell. If trials of antioxidants and iron chelators both are successful, consideration will be given to testing treatments with "cocktails" including both types of compounds.
  •  Animal Model. After great progress using yeast cultures, the FRDA scientific community turned its attention to developing a mouse model so that compounds and techniques not yet deemed safe for use with human patients can be tested on mammals in the laboratory. One classic approach already attempted is that of a "knock out" model - deleting or "knocking out" the Frataxin gene in mice. However, because life cannot be sustained in the total absence of the Frataxin protein, mice with the Frataxin gene deleted on both alleles, do not survive even the embryonic stage. In order to generate a mouse model that is viable and has a disease closely resembling FRDA in a human, it is necessary to reduce significantly the amount of Frataxin the mouse produces while leaving a sufficient amount to sustain life and approximate human symptoms. Consequently, other approaches are being taken, such as developing "knock in" mice in which the Frataxin gene is replaced with a mutant gene, as well as crossing such a "knock-in" mouse with one in which the Frataxin gene has been "knocked out" on one allele. In some cases, the attempt is to transfer human Frataxin genes to mice in hopes of developing "transgenic" mice that approximate the human disorder. Discussion of these approaches at the workshop accelerated the collaboration among the centers involved in developing mouse models. That collaboration continues and will extend to sharing the mouse models once developed, so research around the world can advance rapidly. Due to proprietary rights regarding publishing a scientific breakthrough such as development of a mouse model, patients and families can expect to learn about such an exciting development once it has been published.


 Collaboration is Vital

The collaboration that took place at the FARA/NIH workshop continues on all four avenues of approach above and more. As the research develops further, FARA will facilitate workshops with small groups of scientists making real progress along a particular avenue who need to get together to share insights, consolidate findings and map the road ahead. The collaboration at the Bethesda workshop was electric. Gifted scientists from all over the world were testing their ideas with colleagues they rarely see. The workshop served to further energize them and convince them that their work will result in real breakthroughs. FARA President Ron Bartek asked a key scientific participant at the FARA workshop why, with such a rare disorder, there were so many scientists in that conference room who came from all over the world and were so excited about their work. The answer was promising. The scientist said simply, "All neurological disorders are terribly difficult to solve. We think we can get this one."


 List of Participants

Robert Wilson - Principal Investigator
University of Pennsylvania

Scientific Organizing Committee
Massimo Pandolfo
University of Montreal

Bronya Keats
Louisiana State Univeristy

Michel Koenig
Institute of Genetics & Molecular & Cell Biology

Kenneth Fishbeck

NIH Particpants

Gerald Fishbach
Director, NINDS

Steve Groft
Director, Office of Rare Diseases

Georg Auburger

Robert Baughman

Marian Emr

Ed Grabcyzk

Andrea Gropman

Mark Hallett

Audrey Penn

Tracey Roualt

Phillip Sheridan

Giovanna Spinella

Karen Usdin

Marcia Vital

Peter Von Gelderen

Daniel Waldvogel

Huber Warner

Steve Zullo

Non-NIH Participants

Flint Beal
Weil Medical College of Cornell University

Sanjay Bidichandi
Baylor College of Medicine

Alexis Brice
CPS, France

David Brooks
University of Pennsylvania

R. Stanley Burns
Cleveland Clinic and Foundation

Patrizia Cavadini
Mayo Clinic

Susan Chamberlain
Imperial College School of Medicine

Sergio Cocozza
Federico Ii Univ.

Gino Cortopassi

Marisol De Castro
Hospital Universitaria, La Fe, Spain

Martin Delatycki
Murdoch Institute Royal Children's Hosp., Australia

Alessandro Filla
Federico Ii Univ.

Susan Forrest
Murdoch Institute Royal Children's Hosp., Australia

Goutam Gupta
Los Alamos Natl. Laboratory

Sergei Illarioshkin
Russian Academy Of Medical Sciences

Panos Ioannou
Group Leader, Gene Therapy Group Murdoch Institute Royal Children's Hosp., Australia

Grazia Isaya
Mayo Clinic

Sarn Jiralerspong
Univ. Of Montreal

Jerry Kaplan
Univ. Of Utah

Bronya Keats
Louisiana State University

Gyula Kispal
Institut For Zytobiologie Der Philipps-Unversitat, Marburg, Germany

Sergei Klyushnikov
Institute Of Neurology Russian Academy Of Medical Sciences

Michel Koenig
Institute Of Genetics & Molecular & Cell Biology, Strasbourg

Arnulf Koeppen
Albany Va Med. Ctr.

Jacques Lamarche
Univ. Of Montreal

Roland Lill
Institut For Zvtobiologie Der Philipps-Unversitat, Germany

Lioba Lobmayr
University Of Pennsylvania

David Lynch
University Of Pennsylvania

Carlos Miranda
Univ. Of Montreal

Laura Montermini
Univ. Of Montreal

Keiichi Ohshima
Univ. Of Montreal

Francesc Palau
Hospital Universitaria, La Fe, Spain

Massimo Pandolfo
University Of Montreal

Pragna Patel
Baylor College Of Medicine

Bette Phimister
Nature Genetics

Mark Pook
Imperial College Of Medicine

Michael Ristow
University Of Cologne

Pierre Rustin
Necker Enfants Malades

Naoaki Sakamoto
Texas A&M

Anthony Schapira
Royal Free And Uch Medical School And Institute Of Neurolgy

Joerg Schulz
University Of Tuebingen

Jorge Sequeiros
Universidade Do Porto, Portugal

Julie Smith
Univ. Of Utah

S. H. Subramony
Univ. Of Miss. Med. Ctr.

Franco Taroni
Instituto Nazionale, Neurologico, Italy

Robert Wells
Texas A&M

Myra Wick
Univ. Of Minnesota

George Wilmot
Emory University

Robert Wilson
University Of Pennsylvania

Lee-Jun C. Wong
Georgetown Univ.

Nick Wood
Institute Of Neurology, University College, London

Deniece Roach
Natl. Ataxia Foundation

Donna Gruetzmacher
Natl. Ataxia Foundaton

Fara Facilitators
Raychel Bartek
Ron Bartek
Mary Bode
Grant Curtis
Marilyn Downing
Terry Downing
Fraser Goodmurphy
Rochelle Litke
Marty Litke

Other Attendees:
Joe Carbone
Anita Carbone
Carol Curtis
James Curtis
David Doremus
Samantha Fischman
Adam Fischman


Last Modified April 18, 2011