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ACTRIMS 2022 | Toxic astrogliosis in MS – precision, biomarker-guided combination therapies

Ruturaj Masvekar, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, talks on current and related work regarding toxic astrogliosis in multiple sclerosis (MS). A study published in Nature demonstrated toxic astrocytes in MS lesions, identifying complement component 3 (C3) as a biomarker for toxic astrocytes. Using a commercially available drug library, multiple drugs related to unfolded protein response were found to target toxic astrogliosis – blocking proteosomes or heat-shock proteins. Astrocytes produce and secrete many proteins, with the potential for the misfolding of proteins relating to the development of toxic astrogliosis. C3 was observed to reduce after drug admission – however, C3 is also produced in other CNS cells and, therefore, is not specific. Furthermore, prolonged administration of these drugs could have adverse effects on healthy astrocytes. Dantrolene, a ryanodine receptor inhibitor, has also demonstrated the specific ability to block the induction of toxic astrogliosis. In vivo, specific biomarkers, targeted delivery, and treatment are vital for targeting a specific cell type. Therefore, following analysis, Dr Masvekar describes the serine protease inhibitor A3 (serpinA3) as a highly specific biomarker for toxic astrogliosis in the CNS – that when coupled with dantrolene, allows for the specific targeting of toxic astrogliosis in a clinical environment. This interview took place at the ACTRIMS forum 2022 in West Palm Beach, Florida.