Remyelinating trial on the way…here’s why

Natrajan MS, de la Fuente AG, Crawford AH, Linehan E, Nuñez V, Johnson KR, Wu T, Fitzgerald DC, Ricote M, Bielekova B, Franklin RJ. Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain. 2015 Oct 12. pii: awv289. [Epub ahead of print]

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.

Prof Franklinstein sewed a young and and old mouse together to show that young blood could help old bods repair. This was shown to be due to the macrophages/microglia clearing up the myelin debris. In a gene search they found that the RXR gene appears in remyelination. In this study they show that the RXR gene pathway is decreased with aging but you can stimulate them by stimumlating the RXR receptor….go figure. If you remove RXR the young mice do not clear the debris up. They showed that bexarotene allowed old mice to remyelinate and they are aiming to do a trial in Cambridge with bexarotene. Hope it is aiming to repair newly demyelinated lesions as they have yet to show this approach works in chronic demyelinated lesions and if it is working at the level of clear up them maybe treating relapses and showing better recovery is the name of the experiment.

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  • This seems like an important step to stopping progression too. Maybe a blood test to more accurately tell people if they're transitioning from RRMS to SPMS?

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