Treating achondroplasia: concepts and misconcepts about the potential therapies in development

The first potential therapy to treat the bone growth arrest in achondroplasia, the C-type natriuretic peptide (CNP) analogue BMN-111, is reaching the clinical development stage. 

Remarkably, on the contrary of what happened to other genetic conditions where there is also growth impairment and available therapies, there has been continuous debate within the interested communities regarding the idea of treating achondroplasia. Many questions are very relevant, others, although express genuine and valuable concerns, come involved in misconception.

One of those misunderstandings is about what these new potential therapies for achondroplasia under research are all about. The goal here is to talk about one common idea regarding these new perspectives: will these current identifiable potential therapeutic strategies cure achondroplasia?

To look for an answer to this question we need to understand what achondroplasia is.

Achondroplasia is the result of a misplaced molecule in a gene sequence

Every protein our cells produce is encoded (has its building instruction manual stored) in the DNA. The DNA is a long chain made of a combination of four molecules called nucleotides: adenine, thymine, cytosine and guanine (A, T, C and G). Within the DNA, certain nucleotide combination chains will compose genes while others will give origin to other important regulatory molecules. Think in DNA as a vault storing very important information.

You might remember that proteins are also formed by another kind of chain, made of amino acids. We have reviewed this topic here. You might also remember that when a cell needs to produce a protein to respond to, let’s say, an external stimulus, it will turn on a chemical reaction that will make the cell nucleus build that protein by “opening” the DNA, the vault where the gene is “saved”. The gene will be “read” and “transcribed” (transcription) to a RNA molecule and then, this RNA will be “translated” (translation) into the needed protein. Each nucleotide in the DNA chain receives a number according to its position. A given combination of three nucleotides within a gene will correspond to a specific amino acid in the protein. These combinations are called codons and you can find a nice table showing all codon combinations in this article of Wikipedia (go to the middle of the article to see it). In the protein chain, each amino acid also receives a number according to its position.

The function or functions of a specific protein will be driven by its chemical patterns, which in turn are consequences of the combinations of amino acids in its structure. Each amino acid has distinct electric properties, so if one is mistakenly introduced in the protein chain in place of the right one it may change the entire protein conformation and / or function. This is exactly what happens in achondroplasia.

We learned that the most common mutation that causes achondroplasia is often called G380R. This means that in the position 380 of the fibroblast growth factor receptor type 3 (FGFR3) protein chain there is an amino acid called arginine in place of another one called glycine (try to see it as if it was a lego block chain, each block with distinct colors or forms). When you go to the correspondent position of the codon that is responsible for the amino acid 380 in the gene FGFR3, you will find that this codon, which should be GGA or GGG to encode glycine, has the first G in the position 1138 replaced by an A resulting in one these two codons: AGA or AGG, both encoding for arginine. That’s why the other way to cite the mutation in achondroplasia is G1138A. Furthermore, in achondroplasia, in the rarer cases when there is a C in place of a G (G1138C), you will also find arginine in place of glycine (look at the table mentioned above), so causing the same clinical consequences.

Figure. FGFR3 in achondroplasia

In summary, in achondroplasia there is a chemical mistake in the structure of the FGFR3 gene (in the DNA), which causes the production of a FGFR3 protein bearing a change in its conformation, which in turn makes it excessively active. As FGFR3 is a negative controller of bone growth, its super activity causes bone growth arrest. You can learn more about the genetics of achondroplasia reading this article by Dr William Wilcox group (Foldynova-Trantirkova S et al. 2012)

How do the currently disclosed potential new therapies work?

Although it is already possible to replace or knockdown a defective gene in the lab, to my knowledge, there is no published work to date trying to figure out if this strategy would work in a living animal model of achondroplasia. All the current known therapies under several stages of pre-clinical and clinical development are directed to the protein FGFR3 activity or to counteract its effects by activating other positive bone growth controllers.They are not designed to change the genetic code. This includes all those strategies we have been discussing in this blog, such as CNP, parathyroid hormone, peptides, aptamers and antibodies. Others, such as MK-4 and siRNAs (small interfering RNAs) and again the aptamers would be directed to interfere in the expression of the gene FGFR3, not to change the genetic code itself. In other words, these later strategies would work in the transcription and / or in the translation of the FGFR3 gene. The links above will take you to previous articles of this blog, where you can find more information about these strategies. You could also take a look in the blog’s Reference page, where you can find free access scientific studies about these approaches.

In short, no currently available potential therapy for achondroplasia would change the  DNA of an affected individual. Someone with achondroplasia will remain with achondroplasia, so these treatments will not cure the condition, only will tackle its main consequences. 

Current potential therapies like BMN-111 will not cure achondroplasia. However, they may help improve the many clinical consequences usually seen in affected individuals and, possibly, will result in better bone growth and consequently in a final higher adult height, which is good too.

Finally, as these new potential therapies are not directed to change the genetic code of anyone there should be no concern about them being part of a strategy to eliminate the human genetic diversity, which is a common thought expressed among people who are concerned about them. These potential new treatments should be understood as are any other available therapies for chronic conditions that also affect growth. One excellent example is genetic hypopituitarism (also caused by single switch mutations in one or more genes), which may cause growth hormone deficiency (GH). There is already a therapy for GH deficiency and no one in the world would say that a child bearing this condition should not be due treated because of the genetic diversity.

The real main challenge to come

It seems that therapies for achondroplasia could become broadly available in the near future (3-5 to 10 years, thinking in all currently under research). Now is the perfect time not to discuss about if affected children should be treated or not. Due to the relatively low prevalence of achondroplasia and hypocondroplasia, one can estimate that any therapy for these conditions will be expensive: just take a look at other genetic or rare conditions with similar prevalence. Therefore, in the next years the main challenge facing parents and advocacy groups will be how to grant access to these treatments to all children that could benefit from using them. We should be already preparing for the battle.