U.S. Department of Health and Human Services

Discoveries May Improve Treatment of Mucopolysaccharidosis

Two recent studies in animal models have reported encouraging indings in the quest to improve treatment for people with 
mucopolysaccharidosis. In this group of genetic diseases, the lack of any one of several enzymes used by cells throughout the body to digest and recycle substances they no longer need leads to accumulation of one or more cellular waste products. These undigested substances are stored in the cells, where they cause serious problems that can include weakness, severe pain, brittle bones, intellectual disability, clouding of the cornea of the eye, organ 
failure, and death. Periodic infusions of puriied replacement enzymes, which cells can absorb and utilize, have been developed as therapies for three types of mucopolysaccharidosis: type I, type II, and type VI (MPS I, MPS II, and MPS VI).

While enzyme replacement greatly alleviates many disease symptoms, lengthening and improving quality of life, such therapies are not cures. A major limitation of the approach has been that the replacement enzymes do not reach some of the tissues where they are needed, including bone, cartilage, and brain, which is separated from the blood by the 
so‑called blood‑brain barrier. Therefore, the enzyme therapies provide little or no relief from cognitive and other neurological disease manifestations.

Researchers recently identiied a potential solution to this problem, and reported encouraging results in experiments with mice lacking the same enzyme as people with MPS I. The scientists noted that the blood‑brain barrier is crossed by a small number of other proteins, and identiied the portion of one of these proteins that allows it to move from blood into 
the brain. They then attached the MPS I replacement enzyme to that key part of the blood‑brain barrier‑crossing protein and showed that the resulting hybrid protein reached brain cells of MPS I mice, where it dramatically reduced levels of accumulated cellular waste.

Research from a different group has identiied another potential therapeutic improvement. Researchers have found that bone and cartilage problems in animal models of various mucopolysaccharidoses are similar to those in people with these diseases. They also found that these problems result, at least in part, from inlammation triggered by accumulated cellular waste products. These observations suggest that an anti‑inlammatory medication might lessen some 
symptoms in bone and other tissues inaccessible to replacement enzymes or when enzyme replacement therapy is not available. The researchers, therefore, tested pentosan polysulfate, a medication known to reduce inlammation and promote cartilage growth that is approved by the U.S. Food and Drug Administration for treatment of a painful urologic condition, interstitial cystitis/painful bladder syndrome. When the drug was given to rats with MPS VI, the researchers observed signiicant improvements in bone, cartilage, and tooth structure, as well as some other symptoms. The treated 
rats were also more mobile and behaved more normally than did untreated control animals, even though cellular waste products continued to accumulate in their bodies. Further research will be necessary to determine if modifying replacement enzymes to allow their transport across the blood‑brain barrier or treatment with pentosan polysulfate—alone or in conjunction with other therapies—may be safe and therapeutically beneicial treatment approaches for lysosomal storage disorders. If so, they may one day allow people with these diseases to lead longer, healthier lives.

Wang D, El‑Amouri SS, Dai M, et al. Engineering a 
lysosomal enzyme with a derivative of receptor‑binding 
domain of apoE enables delivery across the blood‑brain 
barrier. Proc Natl Acad Sci USA 110: 2999‑3004, 2013.

Schuchman EH, Ge Y, Lai A, et al. Pentosan polysulfate: a 
novel therapy for the mucopolysaccharidoses. PLoS One 
8: e54459, 2013.