Table of Contents (click to jump to sections)
Conference Summary
Discussion Points
Antioxidants
Sticky DNA
Iron Chelation
Animal Model
Collaboration is Vital
Participants
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.
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- 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.
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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."
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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
Strasbourg
Kenneth Fishbeck
NIH/NINDS
NIH Particpants
Gerald Fishbach
Director, NINDS
Steve Groft
Director, Office of Rare Diseases
Georg Auburger
NHGRI
Robert Baughman
NINDS
Marian Emr
NINDS
Ed Grabcyzk
NIDDK
Andrea Gropman
NHGRI
Mark Hallett
NINDS
Audrey Penn
NINDS
Tracey Roualt
NIH
Phillip Sheridan
NINDS
Giovanna Spinella
NINDS
Karen Usdin
NIDDK
Marcia Vital
NINDS
Peter Von Gelderen
NINDS
Daniel Waldvogel
NINDS
Huber Warner
NIA
Steve Zullo
NIMH
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
Uc-Davis
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
Observers
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
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Last updated February 09, 2005