Longitudinal Study of Bone Disease in Children With Mucopolysaccharidoses (MPS) I, II, and VI

Although children with MPS I, II, and VI who are treated with hematopoietic cell
transplantation (HCT) and/or enzyme replacement therapy (ERT) are now living into adulthood
with good cognitive development, their quality of life is significantly impacted by their
skeletal abnormalities (i.e., kyphosis, scoliosis, genu valgum), joint contractures, pain,
and severe short stature. Additional therapies (e.g., post-HCT supplemental ERT, anti-TNFα
drugs, stop codon suppression drugs, gene therapy) to decrease the burden of skeletal disease
and improve growth are needed. However, prior to these therapeutic studies, control data
quantifying the progression of skeletal disease in individuals with MPS I, II and VI treated
with ERT and/or HCT are needed, along with biomarkers to be used as early predictors of
response to treatment.

Osteoporosis has been described in animal models of MPS. It is unknown whether abnormalities
seen in animal models of MPS can be extrapolated to osteoporosis or increased risk of
fracture in children and adults affected with MPS. Preliminary data suggest that children and
adolescents with MPS I, II and VI have low bone mineral density (BMD) after adjustment for
short stature and abnormal bone geometry and that markers of bone remodeling are
cross-sectionally associated with BMD. It is unknown whether this decreased BMD during
childhood will result in osteoporosis and increased fracture risk in adulthood. Determining
the risk for osteoporosis in MPS I, II and VI has become particularly important as these
individuals are now healthier and more mobile with new and improved treatments and thus have
a greater opportunity for fracture.

Glycosaminoglycan (GAG) deposition has been identified in bone and cartilage in animal models
of MPS. GAG deposition in cartilage has specifically been shown to induce inflammation (e.g.
increased tumor necrosis-alpha [TNF- α ] levels in serum and synovial fluid), chondrocyte
apoptosis, and hyperplasia of the synovial membranes. We have found that serum TNF-α is
elevated in children and adolescents with MPS I, II and VI and is associated with bodily pain
and poor physical function.

Our long-term goal is to identify and test new therapies for musculoskeletal disease in MPS.
The objective of this proposed longitudinal observational study is to document the
progression of skeletal disease and identify biomarkers that either predict disease severity
or could be used as therapeutic targets in individuals with MPS I, II, and VI. The rationale
for this project is to obtain baseline data for future therapeutic clinical trials and to
identify potential therapeutic targets. Our central hypothesis is that skeletal disease will
progress over time and that biomarkers of inflammation, and bone and cartilage turnover, will
predict the severity of skeletal disease over time. Therefore, this study has the following
specific aims (SA):

SA1: To characterize the progression of skeletal disease from childhood into young adulthood
for individuals with MPS I, II and VI. Our hypothesis is that there will be a progressive
decrease in bone health as this population matures into young adulthood due to decreasing
mobility, chronic inflammation, and intrinsic MPS related bone disease.

SA2: To identify prognostic biomarkers of inflammation, bone remodeling, and cartilage
turnover that can predict the progression of skeletal disease and impaired physical function
in MPS I, II and VI. Our hypothesis is that biomarkers of inflammation, bone remodeling, and
cartilage turnover, will be predictive of change in physical function, BMD, range of motion,
hip dysplasia, kyphoscoliosis, quality of life, and height over 5 years.

At the completion of this study we expect to quantify the progression of skeletal disease in
MPS I, II and VI treated with ERT and/or HCT to be used in future therapeutic clinical
trials. In addition, we will obtain biomarkers of skeletal disease progression that could
identify early treatment efficacy. Finally, we will gain further insight into the mechanism
of persistent skeletal disease in MPS that will provide potential therapeutic targets.

Inclusion Criteria:

- Diagnosis of MPS I, II, or VI

- Ability to travel to study center for evaluations.

- Age ≥ 5 years and < 35 years: age at entry into study must be ≥5 years and ≤33 years
to ensure a minimum of 2 study visits.

Exclusion Criteria:

- Pregnancy (will be determined at each study visit)

- Participation in any other study within the past 12 months which would result in
increasing the child's radiation exposure above 500 mrem for the calendar year.

- Participants who cannot comply with study procedures or have other factors that would
inhibit their participation as determined by the PI's discretion.