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| Formula | C27H45NO |
| Molar mass | 399.65 g·mol−1 |
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Olesoxime (TRO19622) is an experimental drug formerly under development by the now-defunct French company Trophos as a treatment for a range of neuromuscular disorders. It has a cholesterol-like structure and belongs to the cholesterol-oxime family of mitochondrial pore modulators. [1] [2]
In preclinical studies, the compound displayed neuroprotective properties by promoting the function and survival of neurons and other cell types under disease-relevant stress conditions. It did so through interactions with two components of the mitochondrial permeability transition pore (mPTP), VDAC and TSPO. [3] In preclinical studies on Huntington's disease, the disease-attenuating effects of olesoxime were attributed to modulating the activity of calcium-dependent proteases called calpains. [4] [5]
A 2009–2011 phase 3 clinical trial in amyotrophic lateral sclerosis did not demonstrate an increase in survival. [6] A 2011–2013 trial in spinal muscular atrophy (SMA) indicated that the compound may prevent deterioration of muscle function. [7] [8] In 2015, the entire olesoxime programme was purchased by Hoffmann-La Roche for €120 million with a view to developing a treatment for SMA. However, in June 2018, faced with technical and regulatory challenges and competition from a potentially more effective drug nusinersen, Roche halted further development of olesoxime. [9]
Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other diseases of this group permit normal adult life with only mild weakness.
Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.
Omigapil is a drug that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The development for PD and ALS have been terminated due to lack of benefit, but Santhera Pharmaceuticals bought the compound for development for the treatment of congenital muscular dystrophy (CMD).
Arimoclomol is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. In 2011 the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS. The European Medicines Agency (EMA) and U.S. Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.
The anterior grey column is the front column of grey matter in the spinal cord. It is one of the three grey columns. The anterior grey column contains motor neurons that affect the skeletal muscles while the posterior grey column receives information regarding touch and sensation. The anterior grey column is the column where the cell bodies of alpha motor neurons are located.
Progressive muscular atrophy (PMA), also called Duchenne–Aran disease and Duchenne–Aran muscular atrophy, is a disorder characterised by the degeneration of lower motor neurons, resulting in generalised, progressive loss of muscle function.
Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.
Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. In humans, the translocator protein is encoded by the TSPO gene. It belongs to a family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR to transport cholesterol into mitochondria, though evidence is mixed.
Xaliproden is a drug which acts as a 5HT1A agonist. It has neurotrophic and neuroprotective effects in vitro, and has been proposed for use in the treatment of several neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease.
In medicine, split hand syndrome is a neurological syndrome in which the hand muscles on the side of the thumb appear wasted, whereas the muscles on the side of the little finger are spared. Anatomically, the abductor pollicis brevis and first dorsal interosseous muscle are more wasted than the abductor digiti minimi.
Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease, is a rare and terminal neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most common form of the motor neuron diseases. Early symptoms of ALS include stiff muscles, muscle twitches, gradual increasing weakness, and muscle wasting. Limb-onset ALS begins with weakness in the arms or legs, while bulbar-onset ALS begins with difficulty in speaking or swallowing. Around half of people with ALS develop at least mild difficulties with thinking and behavior, and about 15% develop frontotemporal dementia. Motor neuron loss continues until the abilities to eat, speak, move, or, lastly, breathe are lost.
Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein in humans.
Trophos was a biopharmaceutical company specialising in the discovery and development of novel therapeutics to treat both orphan neurodegenerative diseases and more prevalent disorders.
Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.
Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial, also known as Protein N27C7-4 is a protein that in humans is encoded by the CHCHD10 gene.
Monomelic amyotrophy (MMA) is a rare motor neuron disease first described in 1959 in Japan. Its symptoms usually appear about two years after adolescent growth spurt and is significantly more common in males, with an average age of onset between 15 and 25 years. MMA is reported most frequently in Asia but has a global distribution. It is typically marked by insidious onset of muscle atrophy of an upper limb, which plateaus after two to five years from which it neither improves nor worsens. There is no pain or sensory loss associated with MMA. MMA is not believed to be hereditary.
Jokela type spinal muscular atrophy (SMAJ), also known as late-onset spinal motor neuronopathy (LOSMoN), is an ultra-rare neuromuscular disorder characterized by muscle twitches and cramps. The symptoms appear in adulthood and gradually progress. The disease is caused by a mutation in the CHCHD10 gene and is inherited in an autosomal dominant pattern. It was first described by the Finnish neurologist Manu Jokela in 2011.
Branaplam is a pyridazine derivative that is being studied as an experimental drug. It was originally developed by Novartis to treat spinal muscular atrophy (SMA); since 2020 it was being developed to treat Huntington's disease (HD) but the trial ended in 2023 with harmful side effects.
Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA) and the first oral medication approved to treat this disease.
C. Frank Bennett is an American pharmacologist. Bennett is currently the Senior Vice President of Research and Neurology Franchise Leader at Ionis Pharmaceuticals. He is a 2019 Breakthrough Prize winner in Life Sciences, which he shared with his collaborator Adrian R. Krainer for the development of an effective antisense oligonucleotide therapy for children with the neurodegenerative disease spinal muscular atrophy.