Notes From Murdoch Meeting on FA Dear INTERNAF participants, Considering the high level of interest of the subject, I think an update on FRDA research and perspectives for treatment was long overdue. I take the opportunity of the report about the Melbourne meeting to do that. First, where are we with research? In brief, investigations are continuing at all levels. At the DNA level, analysis of the properties and effect on gene expression of the GAA expansion (I remind that in FRDA there is a GAA triplet repeat expansion in the first intron of the frataxin gene) is going on. It is now clear that the expansion results in a low level of frataxin (from 3-4% to 20-25% of normal), and the mechanisms are actively investigated in a number of models. At the cellular level, it has been established that frataxin is a mitochondrial protein, expressed at highest levels in the tissues affected by the disease. Hints about its function came from experiments in yeast, indicating that in this organism frataxin prevents iron accumulation in mitochondria. Yeast cells without frataxin become also very sensitive to oxidants, and this is because iron reacts with some oxigen-derived molecules (normally generated in cells as by-products of respiration) to produce highly reactive substances (free radicals) that damage cellular structures. The Fenton reaction, quoted in a message to INTERNAF, is the reaction of iron with hydrogen peroxide that generates the highly toxic hydroxyl radical. Some evidence of disturbed iron metabolism in FRDA patient was already available (e.g. iron deposits in the heart), and additional evidence was found recently (deficiency of some iron-containing enzymes also in the heart). Current research is focusing on investigating if frataxin deficiency in human cells also results in mitochondrial iron accumulation and oxidative damage. Mouse models of FRDA (frataxin deficient mice) are being developed in at least two labs and will be available in several months. These mice will make no frataxin at all, different from the human FRDA patient who still make some protein, so they may be very severely affected or even not viable. We have to wait and see. In addition, blood studies and studies with magnetic resonance imaging and spectroscopy are planned or being done to detect possible anomalies of iron metabolism that can be monitored in patients, and possibly used not only to investigate the disease process, but also to follow up the effect of any experimental treatment. Analysis of mutations is also continuing, including the rare frataxin point mutations, that is DNA abnormalities in the coding sequence for frataxin which cause a deficiency in a different way than the GAA expansion. Concerning FRDA cases without any mutation in the frataxin gene, in my experience (and also reported in published papers) there are rare individuals with a FRDA-like clinical picture whose disease is due to abnormalities in a different, yet unidentified gene on a different chromosome. If there are also cases with different, yet undetected frataxin mutations remains to be established. Concerning perspectives for treatment trials in the not-so-distant future, discussion is going on among the participants to the network created at the Montreal meeting (29 May - 1 June, 1997). In addition, on October 29 some of us had a very interesting meeting in Baltimore in which many issues concerning possible drug trials in FRDA were discussed. Participant, in addition to myself, included Drs. T. Ashizawa (Baylor Coll. of Med., Houston), D. Geschwind (UCLA), H. Paulson (Philadelphia), B. Keats (New Orleans), S. Forrest (representing the Melbourne group), M. Scavina (Dupont Institute, Wilmington), and two hematologists, one from the Dupont Institute and one from U. of Utah. There was a general consensus that any trial with patients should be postponed until more basic research has been carried out. The key points are: a) Determine to what extent the yeast knock-out data can be replicated in human FRDA cells, including evidence of mitochondrial iron accumulation and of increased sensitivity to oxidants; b) Collect evidence of iron accumulation and oxidative damage in patients’ pathological samples. c) Evaluate if iron chelators are effective in cell culture to remove excess iron from mitochondria and to correct any observed defect in FRDA cells; Inclusion and exclusion criteria for a trial, possible drug choices, dosage, and route of administration, evaluation and testing of patients in trials were also discussed. In summary, if research results will confirm that this is a promising avenue, chelator trials may possibly be planned within the next year. I have also to say that some groups would like to go ahead in a shorter time with trials involving only antioxidant drugs, considered much safer than chelators. Antioxidants would not remove any excess iron, but would contrast its effects. I hope this summary helped. Sincerely, Massimo Pandolfo, M.D. Chercheur Agrege, Departement de Medecine, University de Montreal Adjunct Professor, Department of Neurology and Neurosurgery, McGill University Centre Hospitalier Universitaire de Montreal Centre de Recherche Louis-Charles Simard 1560 rue Sherbrooke Est Montreal, Quebec H2L 4M1 Canada Phone (+1) 514-281-6000 ext.8928 (office) (+1) 514-281-6000 ext.8935-6 (lab) (+1) 514-896-4762 (fax) email: massimo.pandolfo@umontreal.ca