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Modulators of the RXR Pathway

Recent work (Cramer et al., Science, 2012) has shown that the retinoid X receptor (RXR) agonist bexarotene can promote increased beta-amyloid turnover, reduce plaques, and reverse Alzheimer's Disease related deficits in mouse models of the disease. Activation of RXR induces APOE gene expression in astrocytes, which in turn increases the amount of ApoE protein produced. Increased ApoE protein levels results in increased rates of amyloid beta turnover. The net effect is a marked reduction of toxic amyloid beta oligomers in the brain.

Unfortunately, bexarotene can have significant side effects, including headache, nausea, vomiting, dry skin, diarrhea, trouble sleeping, increased serum levels of cholesterol and triglycerides and hypothyroidism. There are also quite a number of relatively rare but even more serious side effects.

jps_rxr

Acelot is aggressively seeking novel RXR agonists with minimal side effects. An important feature of this effort is the ability of JPS screening to identify novel compounds targeted to specific pathways of interest and away from related but distinct pathways. For example, Acelot has recently identified numerous novel lead compounds specifically targeting the RXR pathway that will not activate the closely related RAR pathway.

The novel lead candidates are currently being assayed in-vitro at the Neuroscience Research Institute of the University of California at Santa Barbara. The assays will establish the compounds' ability to increase ApoE protein levels in cultured human astrocytes. These investigations will be followed by additional in-vitro and in-vivo assays.

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(This work is funded in part by the National Institutes of Health.)