Olesoxime, a first hope for Spinal Muscular Atrophy (SMA) patients

Neuromuscular junctions - SMA mouse - Thierry Bordet - NSblog- 2

Olesoxime, a first hope for Spinal Muscular Atrophy (SMA) patients

About the author

 Thierry Bordet has more than 15 years of experience leading drug discovery efforts from preclinical research to proof-of-concept across biotech and academic settings. At Trophos, Thierry led various drug discovery programs for motor neuron disorders which culminated in the identification of Olesoxime, the first treatment for Spinal Muscular Atrophies (SMA). He has worked to identify the targets and mechanism of action of this new family of cholesterol oximes and demonstrated their potential utility in a range of neurodegenerative diseases as well as other therapeutic indications. He now moved to the Biotherapies Institute for Rare Diseases (Evry, France) to conduct the development of novel gene and cell-based medicinal products for orphan disorders. Thierry holds a Master in molecular and cellular biology from Ecole Normale Superieure Lyon, and a Ph.D. in neurobiology from the Department of Human Genetics at Cochin Institute (Paris, France).

Everyone in the field heard, early this year, about this French biotech company named Trophos when Roche, one of the world’s largest pharmaceutical companies, announced its acquisition. Beyond the record value of the deal, this is the hope for patients suffering from Spinal Muscular Atrophy (SMA) to see Trophos’ lead compound, Olesoxime, being quickly approved by health agencies as the first medicine for this terrible uncured debilitating genetic neuromuscular disease and become available to all. As one of the pioneers in Trophos, I had the chance to contribute to the discovery and development of Olesoxime, a unique scientific and human experience which gives sense to my commitment to research.

Trophos’ beginnings

I entered in the SMA field when I joined the department of human genetics of Axel Kahn at the Institut Cochin in Paris to develop a gene transfer-based therapy for motor neuron disorders such as Amyotrophic Lateral Sclerosis (ALS also known as Lou Gehrig’s disease or “Maladie de Charcot”) or SMA. At that time, Judith Melki’s team had just discovered few months ago the Survival Motor Neuron (SMN) gene that led to SMA. Because tools to address SMN gene correction in affected motor neurons were missing, we and others proposed that neurotrophic factors, normally preventing motor neuron cell death during embryonic development, might be used as therapeutic agents for these motor neuron diseases. However pleiotropic effects of neurotrophic factors were a true limitation for their systemic delivery in humans. This led Christopher Henderson to propose that small molecules recapitulating some of the neurotrophic factor activities might be identified, when he created Trophos with Olivier Pourquie, Jean-Louis Kraus, Michel Delaage, Antoine Beret, and the funding support of AFM (Association Française contre les Myopathies).

An old-fashioned method for a successful molecule: Olesoxime

Main challenges we had to face at the beginnings of Trophos were, first to develop primary neurons-based models amenable to industrial process for drug screening. While others were repositioning old drugs in ALS, we were the first ambitioning running dedicated medium throughput screening on the target cell, i.e. the motor neuron. We also had to justify to funding bodies and potential industrial partners the rationale for a phenotypic screening approach, a method which seemed so old-fashioned at the time of the explosion of omics in the early 2000s. Our “black-box” approach was nevertheless justified in the absence of validated drug target(s) and poor understanding of disease mechanisms though this was a clear limitation to chemical optimization. Several years later, the success of olesoxime to stabilize motor functions in non-ambulant SMA Type II and III patients definitively gives us reason. Importantly, these positive results validate the neuroprotective approach for SMA where glutamatergic (e.g. riluzole) or GABAergic (e.g. gabapentin) drugs failed, and evidence of the clinical efficacy of SMN modifiers is still missing.

Representative image of neuromuscular junctions in the diaphragm of a 15-days-old SMA mouse showing denervation as evidenced by the absence of synaptic vesicle labelling. Green: Neurofilament M. Blue: synaptic vesicle marker, SV2. Red: rhodamine-alpha-bungarotoxin to mark post-synaptic acetylcholine receptors

Neuromuscular junctions - SMA mouse - Thierry Bordet - NSblog

Rat embryonic motor neurons labelled with a fluorescent vital dye (Calcein-AM)

Embryonic motoneuron - Thieerry Bordet - NSblog

Could Olesoxime be used to treat other disease?

The success of olesoxime in SMA also put in perspectives its failure in ALS patients few years ago. What does this tell us about motor neuron diseases pathophysiology? At that step, we can only make some assumptions. SMA mouse models, including ours, have shown that first lesions in SMA arise at the far extremity of the motor neuron (i.e. at the neuromuscular junction) while motor neuron cell death is a late and slowly progressing event. On the contrary, ALS is a very aggressive and quickly developing disease where patients have already lost an important part of their neuromuscular junctions at the time of diagnosis. This suggests that the therapeutic window to slow down motor neuron degeneration is more favorable in SMA patients. We might also consider ALS as an aging disorder, a condition potentially less prone to neuronal plasticity. This could make the difference, since part of olesoxime’s mechanism of action may arise from its ability to promote nerve regeneration and neurite sprouting. In that sense, results of MUNE (motor unit number estimation) measurements in olesoxime-treated SMA patients will be of particular importance to decipher its mechanism of action. Finally, ALS is a less clinically and pathogenically homogeneous disease condition compared to SMA, a monogenic disorder. Several phenotypes of ALS exist, ranging from pure upper motor neuron disease to pure lower motor neuron disease, with several demographically and prognostically different intermediate forms. This strongly complicates clinical trial study design but this also suggests that one unique drug is probably not sufficient to counteract all pathological mechanisms involved. If progress were done to diagnose ALS earlier, one might reconsider olesoxime in a pleotherapy approach.

For SMA patients, olesoxime is still not a cure but twenty years after SMN gene discovery this is the promise to slow disease progression pending other complementary treatments. A great hope in Roche’s hands now!