This concept is true for achondroplasia. Achondroplasia is rare, with an incidence of one case in 15000 to 25000 births. The first papers describing the gene defect causing achondroplasia were published in 1994 and, in the following years, the main metabolic consequences of the activating mutation of the fibroblast growth factor receptor type 3 (FGFR3) have also been described.
Achondroplasia is a very specific genetic condition. It is caused by one single aminoacid switch in a protein (FGFR3). This protein is basically expressed by one type of cell, the chondrocytes, and is located almost exclusively in one single tissue, a small part of the child bones we call the growth plate, which is responsible for the long bone growth. Even more importantly, due to genetic specificity, there are two kinds of FGFR3, the isoforms b and c (twin molecules bearing a slight difference between them). The chondrocytes express only the c isoform.
The concept of exclusivity is important because one aspect of the best target for treating a genetic condition is to think about the consequences of blocking a natural protein in the body. As I mentioned before, there is a myriad of reactions one single protein can participate to produce different results. Therefore, there is a relevant risk to cause undesired effects when one such protein is blocked. We have to make the question: what kind of complications will arise if we disturb the action of that protein? In this regard, FGFR3 is an exception. The current knowledge of the FGFR3c metabolic pathway shows that there is little if any participation of this enzyme in other reactions beside those in the chondrocyte proliferation and maturation (hypertrophy) rates, making the FGFR3c one excellent target for treatment.
Other genetic conditions, even rarer than achondroplasia already have specific therapeutic options and more are coming. So, what is making the research for the treatment of achondroplasia so slow? There are several reasons for achondroplasia is still waiting for a treatment.
First of all, although the FGFR3c looks like an excellent target, it is difficult to reach. The growth plate, where lie the cells that must be treated, is a strongly protected environment. It does not have direct blood supply, so nutrients, and drugs, must diffuse within the interstitium (or the cell matrix), a dense, electrically charged tissue. Only small molecules, with the right electric charge can reach the chondrocytes. Research becomes more difficult – and expensive.
Second, ACH is not a lethal or devastating condition. Achondroplasia bearers will probably and frequently suffer with orthopedic, neurological, otological complications, will have an increased social burden, but it is unlikely they will die exclusively because of the condition. Again, in the context where it is increasingly difficult and expensive to develop new medicines, a condition like achondroplasia could be seen as excessively challenging and would not attract enough interest.
Well, how can this be managed?
The pharmaceutical specialized literature has been pointing out to a new trend. Big pharma industries are developing new partnerships with the Academy, where new conceptual therapies are being thought about and initially tested. Then, if one new conceptual compound becomes promising, the industry picks it and perform all further testing (pre-clinical an clinical) necessary to make a new medicine reaching people. For those rare or neglected conditions, these partnerships may allow increasing the speed new therapies become available.
Sometimes, these partnerships start as an initiative from the researcher. He or she finds a new molecule with potential to become a medicine and presents it to a sponsor and the compound can be further tested. Here lies the opportunity for those situations where the resources are not unlimited, where patient/family initiatives can help speed up the whole process. By identifying the best potential therapeutic approaches, raising funds for them, we can drive the research and help it to grow stronger and faster.
We now have a broad picture of the mutation, what makes it amenable for a therapeutic intervention and a view of the drug development challenges.
In the next post, we will begin to work with the potential therapeutic strategies. We will take a new picture of the FGFR3 in terms of its natural path, from its production to its fate. Then, we will start looking where, in this path, FGFR3 can be managed.