INTRODUCTION: UCLA researchers in the Department of Orthopedic Surgery have studied a series of anti-stress compounds that ameliorate the genetic defects of patients with Osteogenesis Imperfecta.
BACKGROUND: Over the past decade researchers have begun to discover a common underlying pathway for several diseases, Endoplasmic Reticulum (ER) stress. The endoplasmic reticulum under normal circumstances functions as the site for folding membrane and secreted proteins. However, under pathological stresses like the presence of mutated proteins that cannot fold properly, an imbalance of folding capacity to incoming proteins can cause ER stress. To sense and respond to ER stress, cells signal through the unfolded protein response pathway (UPR). Ultimately, signaling from these pathways leads to two main conditions, promotion of health or death. There has been much recent interest in the link between UPR life/death decisions and human diseases. One disease of growing interest is osteogenesis imperfecta (OI), a skeletal dysplasia caused by mutations in collagen genes that cause ER stress. While the molecular pathway of this disease has had much attention with potential leads, possible treatments to this disease have not been well elucidated.
INNOVATION: UCLA researchers in the department of orthopedic surgery have studied a series of anti-stress compounds that ameliorate the genetic defects of patients with OI. Researchers were initially interested in improving the bone quality of subjects, but through the course of treatment discovered major effects to the pulmonary system. Pulmonary function is of paramount importance in OI patients, and its insufficiency is currently the leading mortality cause in patients. Interestingly, there are no current drug treatments that target the pulmonary system for OI treatment. Through treatment with the anti-stress compounds researchers were able to partially correct ER Stress defects of the lungs in OI subjects. The same principle of treatment should apply to cases of OI and related diseases with pulmonary deficiency associated to ER stress caused by genetic mutations.
POTENTIAL APPLICATIONS:
• The treatment of OI and issues relating to pulmonary insufficiency
• The treatment of other ER stress induced diseases that interplay with pulmonary insufficiency
ADVANTAGES:
• There is currently no treatment strategy for ER stress induced diseases that interplay with pulmonary insufficiency
DEVELOPMENT-TO-DATE:
The anti-stress compounds have been tested in vivo in a series of mouse models that mirror human OI lethal cases and has shown the amelioration of disease phenotypes leading to partial correction of defects pertaining to the disease. These treatments have been shown to rescue perinatal lethality in mouse models of OI, proving its efficiency.