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Mitochondrial abnormalities and demyelination are both known features of the pathology of several neurodegenerative conditions. 3,4 Compounds that address both of these disease processes are promising targets for development of novel pharmaceutical therapies. 5 Olesoxime was initially developed for use in amyotrophic lateral sclerosis (ALS), when it was discovered that the compound enhances motor neuron survival in vitro; has neuroprotective properties and promotes regeneration of injured motor neurons in mouse and rat models; and enhances survival and delays disease onset in transgenic SOD1 mice models of familial ALS. 6 In studies conducted through the European MitoTarget initiative, 7 olesoxime showed promise in slowing the progression of spinal muscular atrophy (SMA), 8 but was ineffective in ALS. 9 Studies of the use of olesoxime in HD remain in the preclinical phase. Preliminary work in the BACHD rat model of HD demonstrated improvements in psychiatric and behavioral symptoms and cognition, and helped repair mitochondrial impairments, but had no effect on motor symptoms. 10 The effects of mutant huntingtin on mitochondria have yet to be fully elucidated, but studies suggest that mitochondrial membrane permeability and fluidity may be increased in HD, leading to defects in mitochondrial respiration. 11,12 Compounds that decrease mitochondrial membrane fluidity may slow neurodegenerative processes within mitochondria, and thereby slow the progression of HD. Copyright © Huntington Study Group 2014. All rights reserved. MANUFACTURER: Trophos, S.A. MOLECULAR FORMULA: C 27 H 45 NO MOLECULAR WEIGHT: 400 g/mol MECHANISM OF ACTION: Olesoxime is a cholesterol-like compound that exhibits neuroprotective properties. Preclinical studies suggest that olesoxime can promote myelination 1 and decrease mitochondrial membrane fluidity in cell and animal models of HD. 2 MEET THE COMPOUND: Olesoxime (TRO19622) Image source: pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9930827 Nguyen, cont... These include the usual RNA interference or antisense oligonucleotide approaches, but we are also working with our collaborators in Leiden on some exon-skipping approaches that have been successful in some studies in Duchenne muscular dystrophy. The idea is that you actually skip an exon where you think there is an important cleavage site, so for example, you could think of skipping a whole region of the calpain cleavage site, or even the CAG repeats. There's also some interesting work in post-translational modification coming from William Yang's lab. I think these are some of the most interesting new strategies coming up now. HD INSIGHTS: What about trials in premanifest HD? Do you think we are ready for those trials? NGUYEN: I think that is the way to go. We probably have a better chance of modifying the disease if we treat sooner rather than later. Whether we are ready or not is a question for clinicians who actually run those clinics, but from what Sarah Tabrizi (see HD Insights, Vol. 1) and Ralf Reilmann (see HD Insights, Vol. 6) have found in TRACK-HD, there seem to be robust changes that could be used as biomarkers to track disease progression. HD INSIGHTS: Any final thoughts on HD? NGUYEN: I think we're at a very exciting time right now for HD research. Clinical studies such as PREDICT and TRACK have given us a lot of information on the natural course of the disease, and prepared us very well for clinical trials. Now we can actually use this information to test more compounds. It is very exciting to be in HD at this moment; I hope that we can find something quite soon. (continued on Page 7...) H D I N S I G H T S HD Insights, Vol. 8 6