Research Update

      As noted in the previous blog, we are developing a new test that will allow us to estimate how fast a child is growing at the time of testing based on measuring by-products of the bone growth process in urine and possibly blood.  The by-products, which we refer to as “biomarkers” of bone growth, are fragments of cartilage collagen molecules (type II collagen and type X collagen) released as bones grow in proportion to the rate or velocity of growth.  Since the initial blog, we have expanded the number of samples analyzed, especially from rapidly growing young infants and we have improved the accuracy of the results.  The test is still under development, but our results so far are quite encouraging.

      To date we find that both type II and type X collagen biomarker fragments correlate well with age of normally growing children.  The new results reinforce previous ones showing that when the biomarker values are plotted against age, the graphs mimic well established growth velocity curves for infants and children with very high values in the youngest infants which drop during the first year and level off after the second or third year.  The results are similar for the type II and type X collagen fragment biomarkers, which is not surprising and actually reassuring that we are measuring products of bone growth.  We also detect levels of the type X collagen biomarker in blood (serum) from a limited number of normally growing infants and children and observe a strong correlation with age as with the urine test. 

      As soon as our testing procedures are optimized, we will begin to measure biomarker levels at the same time that we measure actual growth in a small group of children.  The goal will be to correlate biomarker levels with growth velocity determined from measuring growth over 12 months.  In other words, biomarkers will be measured in the same infants and children we actually measure.  The results from these studies should allow us develop an equation that will convert biomarker levels to growth velocity rates and vice versa.

      To simulate how this might work, we turned to a study that reported how fast Dutch children grow at different ages, which allowed us to project hypothetically how fast our study subjects should be growing at the time the urine samples were collected.  There were a number of differences in how the growth measurements were taken, data was handled and ages were represented, but it is allowed us to make crude correlations between growth velocities estimaged from the Dutch study and our biomarker results.  The results showing sizable statistical correlations between velocity and biomarker levels exceeded our expectations.  These results strongly support our contention that biomarkers will provide and quick and easy way to determine growth velocity that can be used to evaluate bone growth and monitor treatment of bone growth disorders.  

Developing biomarkers to accurately assess bone growth

        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.