Achondroplasia - an introduction to our approach

As discussed under Research, the root cause of achondroplasia is too much “anti-growth” activity of FGFR3 in the cells of growing bones.  That is, increase in FGFR3 activity within the cells of growing bones results in specific signals that reduce or block growth. Several therapeutic strategies have been proposed to reduce this activity, and most are targeted to the cellular networks that carry instructions from FGFR3 to nucleus within the cells. These networks are complex and dispersed throughout the cell. We have discovered a new pathway that bypasses these established networks and potentially allows instructions to be transferred directly from FGFR3 residing on the surface of a cell to its nucleus, where the regulation of genes involved in controlling growth occurs.  We believe this novel pathway mediates many of the anti-growth signals of FGFR3, including those responsible for achondroplasia.  We also believe that defining this new pathway will lead to the identification of new and potentially better targets for therapeutic intervention for achondroplasia.

Indeed, we have already identified one potential target.  A key feature of this new pathway involves cutting of the intact FGFR3 molecule present at the cell surface to produce a small fragment that moves to the nucleus to deliver its anti-growth message, and promotes nuclear signaling of FGFR3.  To our surprise, the machinery that cuts FGFR3 also cleaves a protein implicated in Alzheimer’s disease.  Other than sharing this common protein cutting machinery, the two proteins and also the two diseases are completely unrelated.  In fact, abnormal cutting of this protein in many patients with Alzheimer’s disease has identified this cutting machinery as a therapeutic target for Alzheimer’s disease, which in turn has led to considerable investment by the pharmaceutical industry in drugs to correct the abnormality.

So how is this relevant to achondroplasia?  As we investigated the cleavage of FGFR3, we discovered that achondroplastic FGFR3 is cut abnormally creating a scenario similar to that for Alzheimer’s disease in which abnormal cleavage contributes to disease.  If so, the distinct possibility arises that drugs designed to favorably alter the cleavage of the Alzheimer protein might also normalize the cleavage of FGFR3 and at least partially alleviate the manifestations of achondroplasia.  In economic terms, our findings raise the possibility of leveraging the enormous investment in Alzheimer’s drugs for a novel treatment for achondroplasia. 

Our goal is to move our project from its current stage of initial discovery to the point where it merits further development by industry.  For this we need to define the new pathway in more depth.  We need to demonstrate that this pathway is involved and necessary for normal FGFR3 effects on growing bone, that it is altered in achondroplasia, and that restoration of normal cleavage corrects the disturbance caused by the achondroplasia mutation.  In short, we need to show that the newly discovered pathway influences bone growth, plays a role in achondroplasia and is amenable to therapeutic manipulation. We anticipate reaching these goals over the next 2-3 years.

We will discuss how we are addressing these points in future blogs.  However, for this blog suffice it to say that many of our experiments are being performed in cultured cells.  We have developed and continue to refine assays that measure precisely how much of the cleaved FGFR3 fragment reaches the cell nucleus.  By comparing normal FGFR3 to FGFR3 bearing the achondroplasia and other relevant mutations, we can begin to understand the impact of the mutations on the fate of the cleaved fragments.  We are also setting up assays to determine the precise location of cleavage within the FGFR3 protein and how this is affected by the achondroplasia mutation.  Once this information is known, we will determine if Alzheimer drugs can normalize cleavage and transfer of the fragment to the nucleus. 

We expect there to be direct target genes of FGFR3 in the nucleus.  To identify them, we are using a technique called Chromatin Immunoprecipitation (ChIP).  It will be explained in a future blog.  Identifying even a few FGFR3 target genes will provide valuable insights into how FGFR3 regulates bone growth.  Measuring the expression of these genes will further validate the effects of the achondroplasia mutation and of candidate drugs on FGFR3 functions. 

To complement our cell culture studies, we are also genetically engineering mice to validate the importance of the FGFR3 nuclear signaling pathway in live animals.  FGFR3 in these mice will be tagged to allow microscopic and biochemical detection.  The mice will have normal FGFR3, FGFR3 bearing the achondroplasia mutation, FGFR3 bearing a mutation that blocks cleavage and prevents the fragment from being produced and FGFR3 comprised of only the cleavage fragment destined for the nucleus.  By analyzing and comparing these mice in detail, we will determine the biologic significance of the direct nuclear signaling by FGFR3.  These mice will also be used to test the Alzheimer’s drugs.

As noted above, future blogs will focus on progress within the different aspects of this overall investigation.