Cholesterol-synthesis intermediates for treatment of demyelinating disorders
Dr Stefan Berghoff, Max Planck Institute of Experimental Medicine; Dr Gesine Saher, Max Planck Institute of Experimental Medicine
In autoimmune demyelinating diseases such as multiple sclerosis, lesions need to be remyelinated. The current immunomodulatory treatments of multiple sclerosis, ameliorate inflammation but cannot rescue neurological disabilities. There is an urgent need for therapeutic strategies that also support myelin repair and neuroprotection.
The invention relates to cholesterol-synthesis intermediates as pharmaceutically active agents for use in the prophylaxis and/or treatment of demyelinating disorders such as multiple sclerosis. As LXR agonists, these compounds facilitate the resolution of inflammatory processes and the recycling of cholesterol for myelination. In addition, as cholesterol precursor, they directly support myelin repair. In preclinical trials, per os application ameliorated experimental and inherited demyelinating disease. Patient material showed comparable disease processes as in mice, suggesting that this treatment could have similar positive effects in multiple sclerosis.
Today, around 2.8 million people suffer from multiple sclerosis (MS) with increasing prevalences every year. Current MS treatments are unfortuanetly only modestly effective. Our invention thus provides new opportunities for future therapy.
To further develop this exciting approach, we are looking for a development or licensing partner.
A PCT application was filed in December 2020
As known from diseases such as arteriosclerosis, cholesterol deposits along blood vessels can be harmful. Similar problems occur in neurological diseases such as multiple sclerosis. Here, defects occur in the regeneration of cholesterol-rich myelin sheaths. The normal recycling of cholesterol from defective myelin sheaths by phagocytes is impaired. This leads to the generation of foam cells that virtually “suffocate” from overfilling with cholesterol. Until now, it was not known what prevents phagocytes from making the cholesterol taken up available again. We have discovered that, paradoxically, the synthesis of cholesterol in phagocytes plays a substantial role in this recycling process. The pharmacological support with cholesterol synthesis intermediates improves the regeneration of lesions in the brains of mice. These findings could have implications to treat myelin diseases such as multiple sclerosis.
2) Stefan A. Berghoff et al. (2021) Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis. Nature Neuroscience, DOI: 10.1038/s41593-020-00757-6