Achondroplasia and the new potential clinical therapies: who can benefit from them?

Introduction

Some of the seventeen readers of this blog have been asking about who would benefit from the potential CNP analogue treatment and the other several approaches we have been reviewing here. This is an important question and concern and I think it worth to discuss this topic a bit.

The software of growth is complex

Growth starts with the first cell divisions of the fertilized egg and will last up to the end of puberty, which means less than 20 years, normally. So, growth is a temporary event in anybody's life.

Growth pace and final height are almost readily determined from the beginning by one’s genetic code, with some interference of the environment. When all pieces are working in harmony, the outcome of the software, the genetic program, will be delivered with minimum variance. This program is delivered by an impressive and increasing number of genes and their respective products (mainly proteins and peptides), with very well controlled intensity and timing (1-4). Any disturbance in this program during the growth period, however, can cause growth delay or acceleration. For instance, poor protein diet may lead to low final adult height. Hyperparathyroidism, which is caused by excessive parathyroid hormone, on the contrary, can lead to overgrowth.

The genetic origin of achondroplasia

Achondroplasia is caused by a mutation in the fibroblast growth factor receptor type 3 gene (FGFR3). Because of the mutation, the protein FGFR3, which is built based on the information present in the FGFR3 gene, becomes more active and leads to an imbalance in the regulation of the speed of bone growth (which we mentioned above). As FGFR3 is a speed reducer and is working stronger than expected, bones in the affected individual, and especially the long bones, will grow less than what was programmed for that individual. The result of this imbalance is well known: short limbs, narrow spinal canal, midface hypoplasia, leg bowing, etc. It looks like a simple description of a typical variance of the human body diversity, but the consequences for the affected individual are not. There are many reviews available describing the many common medical complications associated with the bone growth arrest in achondroplasia. To learn more about them I suggest you to visit the guidance published by the American Academy of Pediatrics here (in English) or here (in Spanish / Español). (5)

Growing bones and FGFR3

All the FGFRs are fundamental for the early development of the body until it is pretty formed. Then these proteins, which were produced by all first generations of cells, will keep being produced in a limited number of tissues or organs. In the case of FGFR3, most cells in the body will stop producing it (or at least, in a significant amount). We can say that the main relevant exception is the chondrocyte living within small structures in the extremities of the bones which we call cartilage growth plates. Growth plates are the structures responsible for bone growth. It is important to understand that FGFR3 will have a role in the control of the growth speed while there is an active growth plate. Therefore, when the growth plate closes after the final growth spurt in puberty, the growth control role of FGFR3 will also cease. In other words, when the cartilage growth plate disappears, FGFR3 signaling (activity) in growth loses its relevance.

Straight to the point

The big question is:

Who could benefit from the new potential drug therapies for achondroplasia? Can an adult be treated with one of such potential drugs?

People have been thrilled by the news about the C-type natriuretic peptide (CNP) analogue called BMN-111, which is being tested to see if it could rescue bone growth in achondroplasia.

You might remember CNP is also one of those many controllers of bone growth we mentioned above. It works by reducing the activity of one of the chemical cascades activated by FGFR3 in the growth plate, so it has a positive role in bone growth. You can learn more about CNP visiting this article of the blog.

However, in the same way FGFR3 is relevant for bone growth while there is a growth plate, only those individuals who still have an open growth plate, with living chondrocytes, would be able to benefit from using this kind of treatment. In other words, only children and teenagers could benefit from this kind of therapy.

This means that, unfortunately, an adult won't be able to benefit from using, for instance, the CNP analogue now under development or any other anti-FGFR3 compound, just because of the fact that he/she doesn’t have growth plates anymore.

Consequences

This also explains why any new potential treatment for achondroplasia will have to be tested mainly in children to see if they really work. In this case, tests in adults will be important basically to learn about main short term safety issues with the potential drug and how would be its path in the body.

A word about clinical trials in children

It looks like that in the near future children affected by the FGFR3 mutation will have access to one or more options of therapy to rescue bone growth and prevent the common medical complications of achondroplasia. Nevertheless, before these potential drugs can reach the pharmacy, they will have to be tested to see if they are safe and efficient. There is a lot of concern about putting our beloved children in risk, by exposing them to yet not well known experimental drugs. However, it is now a request from the main regulatory agencies in the world, such as FDA and EMA, that a drug to be given to children must be tested first in children. Furthermore, clinical trials are tightly regulated and there exists strong surveillance by governments, media and citizens on how any clinical study is performed, no matter if in adults or kids.

To learn more about the clinical development of potential drugs you can visit this previous article or you can go  to the FDA website here. You can also visit this FDA webpage to learn more about the additional protection for children in clinical trials.

References

1. Wuelling M and Vortkamp A. Chondrocyte proliferation and differentiation. In Cartilage and Bone Development and Its Disorders. Camacho- Hübner C, Nilsson O, Sävendahl L eds. Karger, Basel. Endocr Dev 2011; 21: 1–11.

2. Mackie EJ et al. The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification. J Endocrinol 2011; 211: 109–21. (free access)

3. Lui JC et al. Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height. Human Mol Gen 2012; 21 (23) 5193–201. doi:10.1093/hmg/dds347.

4. Takarada T et al. Clock genes influence gene expression in growth plate and endochondral ossification in mice. J Biol Chem 2012; 287 (43): 36081–95. doi: 10.1074/jbc.M112.408963.

5. Trotter et al. Health supervision for children with achondroplasia. Pediatrics 2005; 116(3): 771-83. (free access)