This is the first study to show that the PSACH cellular phenotype can be mitigated by RNAi reduction of COMP expression. Most of the mutations that cause PSACH are in the calciumbinding domain of COMP. These mutations cause increased ER stress, reduced calcium binding, interfere with calcium-dependant protein folding and hamper protein trafficking in vitro. COMP is a pentameric protein comprised of five identical monomers assembled in the rER, modified in the Golgi and then exported to the matrix where it is incorporated into the extracellular matrix of the growth plate. COMP mutations have a dominant negative effect because perturbation of the three dimensional structure of the protein activates the Echinacoside unfolded protein response. COMP and other ECM proteins accumulate in the ER associated with numerous chaperone proteins, including CRT, protein disulfide isomerase, Grp94 and BiP. Deconvolution analysis showed that the protein retained in the rER of PSACH chondrocytes is organized into an ordered intracellular matrix and this may hinder the ER clearance mechanisms. Prolonged stress due to protein accumulation in the rER ultimately causes premature chondrocyte cell death. Surprisingly, mice lacking COMP have only minor skeletal anomalies, suggesting that absence of COMP is not detrimental to morphogenesis and skeletal development. It is the disparity between the human PSACH phenotype and COMP null mouse phenotype that led us to investigate RNAi as a potential therapy for COMP-related skeletal dysplasias by eliminating all COMP mRNA. RNAi therapies are being tested in a variety of conditions including, cancer, macular degeneration, movement disorders, heart failure, storage diseases, prion disease, viral infection, chronic pain and addictive-induced behavior. Vascular endothelial growth factor –Norcantharidin targeted siRNA therapies for age related wet type of macular degeneration are the closest to clinical application and have progressed to safety and efficacy clinical trials. Age-related wet type of macular degeneration occurs when excess blood vessels behind the retina interfere with vision.