AB053. Role of inflammation in the mucopolysaccharidoses & review of recent therapies

Abstract: The mucopolysaccharidoses (MPS) comprise a group of 11 related lysosomal storage disorders due to inherited deficiencies of enzymes involved in glycosaminoglycan (GAG) degradation. Each disorder is characterized by the accumulation of specific GAGs and GAG fragments, mostly in connective tissue cells and tissues, resulting in an array of clinical findings that include abnormal bone growth, joint and skull deformities, tracheal abnormalities and other connective tissue disease. Involvement of the central nervous system occurs in some patients, as does involvement of liver, spleen, lung and other organ systems. Enzyme replacement therapy (ERT) is available for four MPS types (I, II, IV and VI) and under development for several others. Bone marrow transplantation also may be undertaken in patients for whom ERT is not available, and gene therapies are being considered for several of the disorders. While each of these therapies may provide substantial clinical benefit, there are limited effects on the bones, cartilage and brain, indicating a need for new research and treatment options. The common clinical presentation of the different MPS disorders suggests that common underlying disease mechanisms are likely to be responsible, and that new drugs targeting these pathways may be of benefit to multiple MPS types. One such drug is pentosan polysulfate (PPS), which is being “re-purposed” to reduce inflammation and GAG storage in MPS. Two small proof-of-concept clinical trials of PPS in MPS patients have recently been completed. This lecture will review the pathophysiology and genetics of the MPS disorders, the current state of MPS treatment, and prospects for future treatments.

Keywords: Mucopolysaccharidoses (MPS); disorder; glycosaminoglycan (GAG); pathophysiology; genetics