抽象的

New advances in the treatment of Friedreich ataxia: promises and pitfalls

Wolfgang Nachbauer, Sylvia Boesch

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease. It affects primarily the nervous system and the heart. Progressive gait and limb ataxia, dysarthria, loss of vibration and proprioceptive sense are characteristic neurological symptoms in FRDA. In approximately 96% of patients FRDA is caused by a triplet guanine-adenine-adenine expansion within the first intron of the FXN gene on chromosome 9q13. Increased numbers of guanineadenine-adenine repeats are suggested to interfere with FXN transcription via heterochromatin-mediated silencing and result in frataxin deficiency in FRDA. Genetic and biological studies support the role of frataxin as a multifunctional protein in iron-dependent mitochondrial pathways. Multicenter, randomizedcontrolled Phase III trials in FRDA failed to prove disease modifying properties of candidate substances until to date. Phase II studies attributed idebenone, a synthetic short chain quinine analogue of co-enzyme Q10, some clinical benefit. Recent Phase III trials, however, testing idebenone have been negative or are still ongoing. Candidate substances currently tested in small randomized controlled or open-label trials are deferiprone, a mitochondrial iron chelator that forms chemically inert molecules by binding to iron, and conventional recombinant human or carbamylated erythropoietins. Both classes of candidate substances are currently under investigation to assess their efficacy and/or safety profile in Phase II trials. Pioglitazone is a peroxisome proliferator activated receptor g molecule currently tested in a 2-year randomized, doubleblind, placebo-controlled safety and efficacy study. Preclinical candidate substances in FRDA are histone deacetylase inhibitors. Promising findings in animal models will have to be replicated in human cellular models such as reprogrammed induced pluripotent stem cells from FRDA patients. A still unmet issue in FRDA is to establish well shaped clinical study designs in small study cohorts within a reasonable time frame. Therefore, large natural history studies as well as the introduction of validated bio- and surrogate markers are essential issues for future clinical trials.