Professor
Center for Cardiovascular and Muscular Diseases
Why do our skeleton and teeth, but not our soft organs, calcify under physiological conditions? And what goes wrong in hypophosphatasia (HPP), a condition in which children display soft bones and premature loss of teeth (and sometimes die) or conditions such as atherosclerosis or chronic kidney disease where our soft tissues calcify or harden inappropriately?
The culprit is an enzyme called alkaline phosphatase, which I have been studying since I first came to Sanford Burnham Prebys (then called the La Jolla Cancer Research Foundation) in 1977.
Through the power of mouse genetics, my lab has shown that a heritable deficiency in alkaline phosphatase (HPP) leads to the accumulation of a molecule called pyrophosphate, which inhibits mineralization and prevents the extracellular matrix in bone from properly forming and hardening. Too much pyrophosphate also prevents the formation of the acellular cementum needed to anchor the periodontal ligaments to the alveolar bone that surrounds and supports tooth sockets.
This knowledge helped us develop a life-saving enzyme replacement therapy for pediatric-onset HPP, approved in 2015. We are now working on therapeutic options for milder, non-lethal forms of HPP to improve skeletal and muscle health.
Our mouse genetics work also revealed that too much alkaline phosphatase in soft tissues can lead to a dramatic decline in pyrophosphate concentrations, which are needed to suppress calcification where it is not wanted. In blood vessels, for example, too little pyrophosphate can result in the development and progression of atherosclerosis or hardening of the arteries, exacerbate chronic kidney disease and create tiny, calcified particles in the eye that are associated with age-related macular degeneration.
Having developed pharmacological inhibitors to tame these upregulated levels of alkaline phosphatase, the focus now is to bring them to the clinic to slow or prevent these severe forms of ectopic or abnormal calcification.
