Chinese Herb Huperzine A-derived Dimers for Osteochondral Repair

The major challenges for osteochondral repair and regeneration have been synovial inflammation and pathological subchondral bone remodelling in knee osteoarthritis (OA). Huperzine A, originally isolated from a Chinese medicinal herb, Huperzia Serrata, was approved by the China FDA as an AChE inhibitor. To augment AChE inhibition potency, a series of homo- or hetero-dimers containing hupyridone, a fragment of huperzine A, were developed. The compounds were found to act locally to protect chondrocytes from inflammatory stimuli and restore the imbalanced bone resorption with formation. They might also function centrally to activate cholinergic anti-inflammatory signaling via neuroimmunomodulation. 

It is hypothesized that the compounds can exert anti-inflammatory effects and create a pro-regenerative environment in favor of osteochondral repair in OA joints. The candidate herb-derived molecules, i.e. hupyridone, bis(12)-hupyridone (E12E) and hupyridone(10)- tacrine (A10E), will be tested in the following aims: Aim 1 is to decipher drug release kinetics after loading onto self-developed injectable scaffolds, and Aim 2 is to examine the efficacy of the dimers in established osteochondral defect rabbit models. 

The data obtained in a preclinical setting of drug release and efficacy will lay a solid foundation for lead optimization and patent filing towards clinical translation.