Olesoxime Targets Calpain and May Lead to New Approaches in Huntington’s Treatment

Olesoxime, a drug shown to have neuroprotective properties, may have beneficial effects in Huntington’s patients through reduction of calpain-mediated huntingtin cleavage, according to the study “The calpain-suppressing effects of olesoxime in Huntington’s disease,” published in the journal Rare Diseases.

Olesoxime is a small molecule derived from cholesterol that exerts neuroprotective functions by preventing the activation of the mitochondrial apoptotic pathway, inducing neurite outgrowth and improving nerve cells remyelination, revealing beneficial outcomes in animal models of neurodegenerative disorders, motor neuron diseases or peripheral neuropathies.

The research team from the University of Tuebingen, Germany, treated BACHD rats, the latest rat model of Huntington’s disease, with olesoxime from the age of 5 weeks and until they reached 13 months, and compared them with placebo-treated rats. Interestingly, the results revealed a significant reduction in Huntingtin (HTT) aggregation and nuclear accumulation, as a result of reduced calpain-mediated proteolysis.

The calpain proteolytic system is a key player in degenerative processes in general and a major contributor to the cleavage of the disease-causing mutant form of HTT into toxic fragments. Therefore, targeting calpain function using olesoxime could be a new approach in the treatment of such diseases.

Using other HD models – a mouse model (HdhQ111) with a mutated form of the huntingtin gene that provides a more precise reproduction of the human genetic conditions with a slow progressive phenotype, and a stable cell line (STHdhQ111) derived from striatal progenitor cells of this mouse model – the researchers were able to reproduce the prominent effects on calpain activation and HTT fragmentation.

Although it is currently under investigation, the researchers led by Huu P. Nguyen believe that olesoxime is involved the control of calcium homeostasis, allowing the regulation of the calcium-dependent protease calpain-1.

Despite the overall beneficial results, olesoxime failed to improve some pathologies with early onset. This is in line with previous reports of two different clinical trials, one on survival with end-stage amyothrophic lateral sclerosis (ALS) and one on motor symptom onset in early stage spinal muscular atrophy (SMA). While the ALS trial had a negative outcome for olesoxime, the trial on SMA patients revealed remarkable beneficial effects, indicating that the olesoxime may be most effective when applied in early phases of disease.

“The new data confirm that olesoxime suppresses calpain activation and HTT fragmentation in vivo, and strengthen its potential as a treatment for HD.” the authors conclude in their study. “Deciphering olesoxime’s exact mechanism of action might be of great value for the understanding of neurodegenerative processes and the development of effective treatments, also, but not only, for HD.”