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M06 Olesoxime Treatment Inhibits The Formation Of Mhtt Fragments Through Suppression Of Calpain Activity, And Leads To Behavioural And Neurological Improvements In The Bachd Rat
  1. LE Clemens1,
  2. JJ Weber1,
  3. TT Wlodkowski2,
  4. L Yu-Taeger1,
  5. M Michaud3,
  6. JCD Magg1,4,
  7. NL Casadei1,
  8. C Calaminus5,
  9. S Eckert6,
  10. J Eckmann6,
  11. A Weiss7,
  12. G Eckert6,
  13. B Pichler5,
  14. T Bordet3,
  15. R Pruss3,
  16. O Riess1,
  17. H Phuc Nguyen1
  1. 1University of Tuebingen, Institute of Medical Genetics and Applied Genomics, and Centre for Rare Diseases, Calwerstrasse 7, 72076 Tuebingen, Germany
  2. 2Heidelberg University Medical Center, Division of Pediatric Nephrology and KFH Children’s Kidney Center, Center for Pediatrics and Adolescent Medicine, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany
  3. 3Trophos SA,Parc Scientifique de Luminy Case 931, 13288 Marseille Cedex 9, France
  4. 4German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 27, 72076 Tübingen, Germany
  5. 5University of Tuebingen, Department of Radiology, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Roentgenweg 13, 72076 Tuebingen, Germany
  6. 6Goethe Universität Frankfurt am Main, Pharmakologisches Institut Für Naturwissenschaftler, Max-Von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
  7. 7IRBM Science Park SpA, via Pontina Km 30,600, 00040 Pomezia, Italy


Background Proteolytic cleavage of the mutant huntingtin protein (mHtt) leads to toxic N-terminal mHtt fragments, which are known to disrupt mitochondrial function. Olesoxime, a small cholesterol-like molecule, targets mitochondria and has demonstrated therapeutic efficacy in a variety of disease models. Recent clinical investigations revealed exciting results in spinal muscular atrophy patients, where olesoxime was found to be the first drug to efficiently block the progression of motor deficits in a clinical type II study. Furthermore, it was found to increase the survival of primary striatal neurons overexpressing mHtt, suggesting therapeutic potential also for HD.

Aims To evaluate the therapeutic potential of olesoxime in the BACHD rat model of HD.

Methods Olesoxime was supplied to BACHD rats via drug-loaded food pellets from the age of 5 weeks on, and the rats’ behaviour was studied for 12 months. Brain atrophy was investigated with MRI at 13 months. Mitochondrial parameters, mHtt cleavage and aggregation were measured in brain lysates ex vivo.

Results We found olesoxime to specifically ameliorate psychiatric and cognitive disturbances of BACHD rats, to increase frontal cortex thickness and to improve mitochondrial function. Very interestingly, the beneficial effects seemed to be mediated by a downregulation of calpain activity, thereby drastically reducing the formation of mHtt fragments and aggregates, and increasing soluble mHtt levels.

Conclusions Our study reveals new insights into olesoxime’s mechanism of action and highlights olesoxime as a novel tool for reducing toxic mHtt fragments.

  • Olesoxime
  • BACHD rat
  • mHtt cleavage
  • calpain
  • aggregates
  • mitochondria

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