Pathogenesis of Bone Disease in Mucopolysaccharidosis Disorders

Mucopolysaccharidosis (MPS) disorders are genetic diseases that result from deficient activity of enzymes that degrade glycosaminoglycans. Bone disease is prevalent amongst many types of MPS, the consequences of which are particularly severe in the spine, where vertebral abnormalities may lead to spinal cord compression, airway obstruction and deformity. Current systemic treatments for MPS show limited efficacy in correcting spine disease. Our lab has shown that a defining feature of spine disease in across multiple types of MPS is the failure of vertebral bones to calcify normally during growth. This results in the persistence of cartilage in place of bone, and compromises the mechanical stability of the spine. Our overall aim in this study is identify common mechanisms underlying abnormal bone formation across multiple MPS disorders. Using the naturally occurring canine models, we will conduct whole transcriptome next generation screening studies to identify the key regulatory genes that are disrupted in developing MPS bones, and we will directly screen cellular responses to molecules that regulate bone development. Establishing common pathological mechanisms of bone disease across multiple type of MPS will facilitate development of novel treatments that are highly likely to be relevant for many of the 11 enzyme deficiencies of the MPS family of disorders that affect children.

–¬†Lachlan Smith, PhD

two years @ $30,000 each year
University of Pennsylvania Philadelphia, PA