Preclinical Study of NK1 Antagonist VLY-686 in Prevention and Treatment of Injury Induced Heterotopic Ossification in NSE-BMP4 Transgenic Mouse Model

We have established the only currently available animal model that can reliably and closely recapitulate the major phenotypes of FOP as well as hallmarks of common acquired HO. This transgenic mouse line has been a useful tool for studying different mechanistic aspects of HO, such as the nature of the events that trigger HO, the type of cells that respond to the trigger by differentiating along the osteogenic lineage, and the mechanisms underlying the spread of HO. Our recent study found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and also in three independent mouse models of HO (BMP4 matrigel injection, conditional expression of caALK2 and Nse-BMP4 transgenic mice). Null mutations of the preprotachykinin gene encoding SP prevent HO. Ablation of SP+ sensory neurons, treatment with an antagonist of SP receptor NK1r (RP-67580), deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibits injury-induced HO. These observations established a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and suggested that NK1 antagonist could be a promising treatment and prevention of HO.