Meet the Compound: Olesoxime (TRO19622)

compound

Image source: pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9930827

Manufacturer: Trophos, S.A.

Molecular Formula: C27H45NO

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 myelination1 and decrease mitochondrial membrane fluidity in cell and animal models of HD.2


 

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.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.

In a recent study,2 Eckmann and colleagues found that olesoxime successfully decreased mitochondrial membrane fluidity in vitro, and in vivo in mouse and rat models of HD. The researchers posited that the decreased mitochondrial membrane fluidity in BACHD rat brains may be due to increased membrane cholesterol levels. Defects in brain cholesterol metabolism and synthesis have been identified as potential mechanisms for neurodegeneration in HD.13 Dr. Rebecca Pruss, Chief Scientific Officer at Trophos, commented “These results highlight the central role mitochondria play in neurodegenerative diseases…and the need for therapies that restore mitochondrial function in pathophysiologically stressed cells. Olesoxime… could be such a compound; it targets mitochondria and maintains their integrity in stressed cells thus preventing the release of mitochondrial pro-apoptotic factors such as cytochrome c and apoptosis inducing factor… maintaining energy levels and calcium homeostasis. Olesoxime already has a positive clinical track record demonstrating its tolerance, safety and recently its efficacy in spinal muscular atrophy patients; therefore, olesoxime seems to be a promising neuroprotective treatment potentially reducing the effects of huntingtin mutations leading to HD.”table 1


 

1 Li Y, Zhang Y, Han W, Hu F, et al. TRO19622 promotes myelin repair in a rat model of demyelination. Int J Neurosci. 2013 Nov; 123(11):810-822.

2 Eckmann J, Clemens LE, Eckert SH, Hagl S, et al. Mitochondrial membrane fluidity is consistently increased in different models of Huntington Disease: restorative effects of olesoxime. Mol Neurobiol. 2014 Mar 18. [Epub ahead of print]

3 Chen CM. Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington’s disease. Chang Gung Med J. 2011 Mar-Apr; 34(2):135-152.

4 Urrutia PJ, Mena NP, Nunez MT. The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol. 2014; 5:38.

5 Mehrotra A, Sandhir R. Mitochondrial cofactors in experimental Huntington’s disease: behavioral, biochemical and histological evaluation. Behav Brain Research. 2014 Mar 15; 261:345-355.

6 Bordet T, Buisson B, Michaud M, Drouot C, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exper Ther. 2007 Aug; 322(2):709-720.

7 Trophos announces conclusion of MitoTarget Consortium, achieving advanced understanding of neurodegenerative diseases. Media release. 2012 Jul 31; trophos.com/news/pr20120731.htm.

8 Trophos will present results of pivotal phase II/III study of olesoxime in spinal muscular atrophy patients at the American Academy of Neurology (AAN). Media release. 2014 Apr 28; trophos.com/news/pr20140428.htm.

9 Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, et al. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol. 2014 Mar; 21(3):529-536.

10 Clemens LE, Wlodkowski T, Eckmann J, Eckert S, et al. P06 Olesoxime improves specific features of the HD pathology. J Neurol Neurosurg Psychiatry. 2012 Sep 1; 83(Suppl 1):A53-A54.2013.

11 Quintanilla RA, Jin YN, von Bernhardi R, Johnson GV. Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Molecular neurodegeneration. 2013; 8:45.

12 Labbadia J, Morimoto RI. Huntington’s disease: underlying molecular mechanisms and emerging concepts. Trends Biochem Sci. 2013 Aug; 38(8):378-385.

13 Valenza M, Leoni V, Karasinska JM, Patricca L, et al. Cholesterol defect is marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J Neurosci. 2010 Aug 11; 30(32):10844-10850.

14 Magalon K, Zimmer C, Cayre M, Khaldi J, et al. Olesoxime accelerates myelination  and promotes repair in models of demyelination. Ann Neurol. 2012 Feb; 71(2):213-226.

15 Sunyach C, Michaud M, Arnoux T, Bernard-Marissal N, et al. Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharm. 2012 Jun; 62(7):2346-2352. Sci. 2013 Aug; 38(8): 378-385.

16 Gouarné C, Giraudon-Paoli M, Seimandi M, Biscarrat C, et al. Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF. Br J Pharmacol. 2013 Apr; 168(8):1975-88. doi: 10.1111/bph. 12094.Neuropharm. 2012 Jun; 62(7):2346-2352. Sci. 2013 Aug; 38(8):378-385.