As apparent from recent scientific publications and as discussed
in blogs elsewhere in Growing Stronger, the prospects for growth stimulating
therapy in achondroplasia are advancing at a fast pace. Clinical trials for the BioMarin analog of
CNP are underway and other treatment strategies are being investigated in mouse
models of achondroplasia, so-called preclinical studies. So the longstanding dream of normalizing bone
growth partially or even fully in achondroplasia is beginning to come into
focus.
This progress, however, also introduces new challenges not
previously faced by patients, parents and physicians dealing with
achondroplasia or potentially with other skeletal forms of short stature for
which treatment has not been available.
A major challenge is measuring a child’s growth response to treatment. Accurate measurement of growth rate, i.e.,
growth velocity, is essential to determine if a therapy works, the optimal dose
and delivery protocol for a given therapy, if one therapy works better than
another and so on.
Unfortunately, clinical methods currently used to measure
bone growth velocity are not very sophisticated and rely on measuring
incremental growth usually as length or height over many months, typically 6
months or more. This practice is
recognized as less that ideal, but accepted because better and especially
faster methods do not currently exist. To
meet this need, we are developing a completely new test to accurately measure
bone growth that has the potential to reduce the time needed to determine bone
growth velocity from months to days. We
expect it to become a valuable tool in the clinical management of short
stature.
Our new test is based on measuring by-products of the bone
growth process in urine and/or possibly blood. Very briefly, linear bone growth
occurs at the ends of bones through a process in which future bone is first
generated as cartilage template that is subsequently degraded and replaced by
bone. The process is called “endochondral
ossification” and its components are tightly linked and temporally matched to
produce smooth and continuous bone growth.
Importantly, the speed of endochondral ossification determines the rate
of bone growth for individual bones and collectively for overall skeletal
growth.
Our new test will sample endochondral ossification by
measuring its cartilage breakdown products released during template degradation
and predict growth velocity from the relative abundance of these products. We are using fragments derived from cartilage
collagens – types II and X collagen – to serve as bone growth “biomarkers” and
are measuring them in urine and blood.
Our results to date show that small fragments from both types
II and X collagen can be detected in both blood and urine and their abundance
correlates well with age, the highest levels are found in youngest infants who
by inference are growing the fastest. We
are currently optimizing the detection assays and will soon begin to compare
sampling strategies to determine if urine or blood or some combination is most
informative. We hope in the near future
to carry out longer term studies to establish the relationship between
biomarker levels and growth velocity calculated conventionally from measured
incremental growth.
More information about how we intend to correlate biomarker
levels with measured growth in height and how we plan to use the biomarker test
to monitor responses of children with short stature to growth stimulating
therapies will be addressed in future blog entries.
