Oxysterol Therapeutics®

Bone:

Oxysterols are comprised of a family of oxygenated derivatives of cholesterol that are present in the circulation, and in human and animal tissues. A role for specific oxysterols has been implicated in various physiologic processes including cholesterol metabolism, cellular differentiation, inflammation, apoptosis, and steroid production. The main identified receptors for certain oxysterols, that upon activation result in regulation of the transcription of target genes, are the liver X receptors (LXRs). However, many of the effects of oxysterols are not entirely explained by LXR activation, including their osteoinductive and anti-adipogenic effects on mesenchymal cells. We recently showed that the effects of specific oxysterols are mediated mainly through the transient activation of Hedgehog (Hh) signaling pathway in mesenchymal cells, a novel and previously unrecognized finding. In preclinical studies we found that osteogenic oxysterols robustly stimulate new bone formation in animals in models of spinal fusion and maxillofacial and cranial bone regeneration.

 

Cancer:

In addition to stimulating bone formation, we demonstrated that a different class of oxysterols, that differ in molecular structure from the osteogenic oxysterols, act as potent inhibitors of Hh signaling and clonogenic growth of various cancer cells in vitro and in vivo. In addition, these small molecules inhibit the response of stromal cells to Hh proteins derived from tumor cells in vitro. Unlike Smoothened antagonists (inhibitors of Hh signaling developed by other biotech/pharmaceutical companies), oxysterols inhibit aberrant Hh signaling induced downstream of Smoothened and may therefore be effective against a greater number of Hh pathway-mediated cancers.

The unique characteristics and advantages of oxysterols, as well as their potential for local and systemic delivery, relatively inexpensive large-scale synthesis, and anticipated lack of immunogenicity, prompted us to undertake further development into future therapeutic agents for use in targeting a variety of human diseases including cancers, bone defects, and osteoporosis. Accordingly, we have studied and continue to study structure-activity relationships for oxysterols.  As a result of proprietary knowledge that we have gained, we have been able to synthesize novel oxysterols with significantly improved profiles compared to their naturally occurring counterparts and we continue to generate a pipeline of oxysterols for future development into therapeutic agents.

 

A Promising Platform:

The unique characteristics and advantages of oxysterols, as well as their potential for local and systemic delivery, relatively inexpensive large-scale synthesis, and anticipated lack of immunogenicity, prompted us to undertake further development into future therapeutic agents for use in targeting a variety of human diseases including cancers, bone defects, and osteoporosis. Accordingly, we have studied and continue to study structure-activity relationships for oxysterols.  As a result of proprietary knowledge that we have gained, we have been able to synthesize novel oxysterols with significantly improved profiles compared to their naturally occurring counterparts and we continue to generate a pipeline of oxysterols for future development into therapeutic agents.