I started this article after reading a recently published study in which researchers used a statin to target bone growth impairment in a genetic disorder (1). The results of that study bring more evidence for the potential role of statins for the treatment of achondroplasia. While I as writing I realized the topic was very technical (take a look on the third paragraph!), so I decided to add more information to explain some of the concepts I was describing. And then pictures, and more explanations. Well, after reviewing the complete text, I see that it is broader than what I have initially planned and became a new review of the therapeutic landscape, with a focus on the use of statins for the treatment of achondroplasia.
Although I tried to translate hard technical jargon to an easier text, it is possible that for newcomers the language may sound difficult to understand. As all concepts summarized here have already been reviewed in the blog, if you had trouble to follow this text, you could try reading older articles before continuing on this one (try the first ones from 2012) as they can still be considered updated and could offer you more knowledge about the topics mentioned here. Additionally, you will see that I placed links to several blog's articles and external sources throughout the text for those more curious readers. I hope you won't feel bored...
Let's go.
Introduction
RASopathies are a family of genetic disorders caused by mutations in enzymes that modulate the activity of the MAPK pathway, a group of enzymes which is also one of the most important chemical pathways impacted by the fibroblast growth factor receptor 3 (FGFR3) mutation in achondroplasia (reviewed here). A new study exploring the use of statins to treat bone growth retardation in one of the RASopathies has just been published (1). In this study researchers found that statins could be candidates for the treatment of the growth retardation seen in that RASopathy. How does this relate to achondroplasia?
However, before talking about this study let's pick a few basic concepts about achondroplasia and the therapeutic landscape to help us understanding the potential role of statins in the treatment of achondroplasia.
Basic concepts
Chondrocytes, the drivers of bone growth
Chondrocytes are very specialized cells that live inside the growth plates, tiny cartilaginous layers present in the extremities of the long bones in growing bodies (so only in children and teens) (Figures 1-3). The bone growth plate is a very tight and dense tissue without direct blood flow where only small molecules are able to circulate with some freedom (save this info for later!) (2,3).
Chondrocytes within the growth plate drive bone growth by following a highly controlled growth program governed by many molecules produced locally (such as FGFR3 and C-type natriuretic peptide (CNP)) and elsewhere in the body (such as hormones like growth hormone (GH) (3). Upon the influence of these many agents, chondrocytes go from a resting state to a "proliferation frenzy" (multiplication) followed by very significant cell enlargement (what is called hypertrophy) (Figure 2). When fully enlarged, chondrocytes are substituted by osteoblasts (the bone builder cells) and their growth plate zone gives place to new bone (Figure 2). The growth plates close under influence of hormones by the end of puberty (Figure 3) (3).
Figure 1. Growth plate.
Figure 2. Inside the growth plate.
Figure 3. Fate of the growth plate.
FGFR3, a cell antenna
FGFR3 is a kind of receptor antenna placed on the chondrocyte surface (the cell "roof") that receives signals from outside the cell and transmits them to the cell nucleus. It is quite like an antenna dish receiving satellite TV signals and, through cables, taking them to the receiver and finally to your TV in the family room (Figures 4-6). The signal receiver "translates" the signals coming from the antenna into the form of movies, TV shows, news, etc. (the output), according with the kind of signals received.
In the chondrocyte, according to the signals it receives from its antennas (and there are lots of them on the cell surface), the cell nucleus will also respond with different outputs.
While the dish antenna captures/receives signals from satellites in the form of invisible waves, cell signals are transmitted through chemical reactions. FGFR3 is a receptor that accepts only signals coming from molecules (the ligands) called fibroblast growth factors, or FGFs. When a FGF binds to FGFR3 outside the cell, there is a transfer of an electric charge, which in turn activates another chemical reaction inside the cell, in a domino chain-like way (the signalling pathways; Figure 7, Video 1).
Figure 4. FGFR3 structure.
Figure 5. FGFR3 is like a cell antenna.
Figure 6. FGFR3 drives signals from outside the cell to the nucleus inside the cell.
FGFR3 is a chemical brake in chondrocytes
In chondrocytes, signals coming from FGFR3 give instructions to the cell nucleus to reduce the cell multiplication pace. If these signals are transmitted in the right intensity they help chondrocytes to control the "proliferation frenzy" mentioned above, and this is important because there are several other signals telling the chondrocyte to multiply non-stop, which would cause bone growth problems (3).
Therefore, FGFR3 is a key regulator of bone growth, acting as a brake to balance the effect of other antennas which work like bone growth accelerators. In simple words, when it receives a signal from outside the cell, FGFR3 "tells" the nucleus of the cell: hey, stop multiplying, take a nap!".
FGFR3 and achondroplasia
While in normal conditions FGFR3 helps bones to grow in a balanced rhythm, in achondroplasia FGFR3 suffered a mutation (a change in its structure) and is overactive, making the brake too heavy, blocking the normal growth pace. It keeps sending signals to the cell nucleus asking it to stop multiplying even when not needed. Under the effect of the mutated FGFR3, chondrocytes enter in a kind of hibernation status, they stop multiplying and growing (3). This is crucial because chondrocytes' abilities to grow in number (proliferation) and in size (hypertrophy) are the key phenomena that drive bone growth. More specifically, the size and number of enlarged chondrocytes in the hypertrophic zone are considered the most important for normal bone growth.
How does FGFR3 send signals to the cell nucleus?
As we saw above, FGFR3 works transmitting chemical signals to the chondrocyte cell nucleus through several “cables”, called signaling pathways (Figure 7, Video 1). Although the number of "cables" is high, it seems that for chondrocytes the main FGFR3 "cables" are the MAPK and the STAT1 pathways (Figure 7) (3). MAPK is the pathway formed by Ras-Raf-MEK-ERK enzymes (Figure 7, on the right; reviewed here).
Knowing how FGFR3 exerts its functions in chondrocytes helps researchers to design and create strategies to control the excessive FGFR3 signaling, restoring bone growth or bringing it close to the normal rhythm (see below).
Video 1 is a ~14 min long animation showing how the body works to heal a skin wound, but you just need to watch the first ~7 min to see the activation of a signaling pathway. Basically, this animation shows how extra-cellular signals activate cells called fibroblasts to begin the wound healing process. The basic mechanism is valid for chondrocytes, although the outputs would be different from what we see in the animation.
Figure 7. FGFR3 signaling pathways.
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| Activation of FGFR3 leads to activation of STAT1 and MAPK (Ras-Raf-MEK-ERK) pathways, which respectively inhibit chondrocyte proliferation and hypertrophy (differentiation). From Su N et al. 2014. This image used only for educational purposes. |
Video 1. Activation of receptor tyrosine kinases (RTK) and their chemical pathways.
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| This is a ~15 min long animation in English showing how cells called fibroblasts help starting healing a skin wound. FGFR3 is a RTK and the cell processes presented here are similar to what happens in any cell, including chondrocytes. However, remember that in chondrocytes, upon the activation of FGFR3, the cell stops to multiply. Source: DNA Learning Center by Cold Spring Harbor Laboratory. Reproduced here for educational purposes only. |
Treating achondroplasia
Strategies to treat achondroplasia target several different spots in the communication between the signals coming from outside the chondrocyte (the TV signal) and the chondrocyte nucleus (the TV receiver).
If any strategy wanted to be successful it would need to inhibit, block or reduce the intensity of the signals the mutated FGFR3 sends to the chondrocyte nucleus, so the cell could resume its normal growth program. This is relevant because, beyond likely increasing final height, these potential therapies may help reducing limb disproportion and several common neurological and orthopedic complications as well as improving quality of life of affected individuals. Let's give examples using some approaches currently under investigation. We will go through the communication channels from outside to inside the cell.
Note: although it is already possible to correct the FGFR3 mutation (gene editing) (4), to my knowledge there has been no new publications in this field so far. All strategies listed here target FGFR3 signaling only so they won't "cure" achondroplasia. This simply means that an individual with achondroplasia treated with one of them would still have achondroplasia, regardless of having normal, or close-to-normal, bone growth.
Ligand Traps
- TA-46
What does it mean for achondroplasia? In a mouse model of achondroplasia, TA-46 was able to prevent FGFs to activate the mutated FGFR3, leading to a significant reduction of FGFR3 signaling (so, reducing the volume of signals that reached the cell nucleus through FGFR3), which in turn restored bone growth (5). In simple words, the TV signals wouldn't reach the TV antenna (FGFR3), and the TV wouldn't show any program coming through the FGFR3 antenna. The biotech exploring TA-46 announced they would be starting a phase 1 clinical trial in the first quarter of this year.
- Aptamers
In the context of achondroplasia, although FGF2 is present in the growth plate, FGF9 and FGF18 are considered more relevant for FGFR3 activation in the chondrocyte (3), so we will need to see if RBM007 is the right aptamer for achondroplasia (where are the studies showing so?).
Aptamers can be designed to bind any molecule. For example, one could be designed to bind the exterior part of FGFR3 in the same way an antibody does (below).
Figure 8. Ligand trap strategy.
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| Soluble FGFR3 (sFGFR3, TA-46) fluctuates within the growth plate, close to the chondrocyte cell surface and attracts nearby FGFs. FGFs bound to TA-46 can't activate the "natural" FGFR3 attached to the cell surface. Source: Therachon. Reproduced here for educational purposes only. |
Antibodies
Antibodies are molecules created by our immune system to help eliminate foreign agents and substances that invade the body. Nevertheless, it is possible to create specific antibodies against almost any target you can imagine and this has been done with FGFR3. There are several antibodies against FGFR3 described in the literature and one, B-701 (formerly R3Mab; reviewed here) (7), is being explored by a biotech for some kinds of cancer driven by FGFR3 (here) and achondroplasia (here).
In achondroplasia, B-701 would bind to FGFR3, preventing the docking of FGFs, so it would work like an umbrella over the FGFR3 antenna (Figure 9). In other words, upon the antibody binding to FGFR3, FGFs (the TV signals!) would not be able to reach and activate the antenna, so their signals wouldn't reach the chondrocyte nucleus.
An ongoing question is whether an antibody, usually a large molecule, would be able to reach FGFR3 within the growth plate, a very dense tissue (as we saw above) since only small molecules are able to penetrate and circulate within the growth plate (2). Although several anti-FGFR3 antibodies have been developed to date, I couldn't find any study clearly showing any of them explored in the context of the growth plate. The developer of B-701 claims to have completed pre-clinical studies (here), but nothing has been published about them yet.
Figure 9. An Antibody covers FGFR3 to prevent the binding of FGFs.
Tirosine kinase inhibitors (TKIs)
TKIs are small molecules that have affinity to some special spots in the part of the body of the cell antennas that lies inside the cell, where the chemical reactions that will turn on the chemical pathways happen (called tyrosine kinase domains).
Almost all research done with TKIs is focused on cancer therapy, since cancer cells use antennas such as FGFR3 to drive their own growth, multiplication, survival and metastatic capability. By blocking relevant cancer cell antennas, new therapies against cancer have been showing to be more effective than older ones.
Take a look on Figure 4 again to see where the tyrosine kinase domain is located. These chemical reactions taking place in this internal domain drive the subsequent signal transmission from FGFR3 to the nucleus.
Watch Video 2 to see how the TKI imatinib works. The antenna targeted by imatinib is not FGFR3, but the mechanism of action is quite the same.
Video 2. Mechanism of action of imatinib, a TKI.
Many TKIs with action against FGFRs have already been described (reviewed here), and one of them, BGJ398 (infigratinib), is now being explored specifically in achondroplasia after a recent study showed that it restored bone growth in an animal model without major safety concerns and in doses far below those needed to treat cancer (8).
Similarly to imatininb (Video 2), infigratinib binds to those spots in the intracellular part of FGFR3 and blocks the ability of the activated receptor to forward the signal transmission to the cell nucleus. In other words, FGFR3 keeps receiving signals from outside, but can't deliver them to the cell nucleus.
CNP and CNP analogues (ex.: vosoritide, TransCon-CNP)
Vosoritide is an improved copy of a natural molecule produced by our body called CNP. CNP works by naturally controlling the amount of signals that FGFR3 transmits to the cell nucleus, inhibiting the MAPK pathway (Figure 9). In several studies in animal models (reviewed here) it showed significant improvement of bone growth. The phase 2 study with vosoritide showed around 40-50% improvement in bone growth velocity in children under treatment over 30 months (here). It is currently in phase 3 clinical trial in children with achondroplasia (here). TransCon-CNP, another CNP analogue is planned to enter clinical development soon (here).
Meclozine/meclizine
Meclozine is an old motion sickness (anti-histaminic) drug that has been showed to work similarly to CNP, inhibiting the MAPK pathway in animal models of achondroplasia, partially restoring bone growth (Figure 9) (9-12). Last year, during the International Skeletal Dysplasia Society meeting (ISDS 2017), the Japanese group working with meclozine announced plans to start a phase 1 study by the end of 2017 or beginning of 2018, but there has been no formal indication that this study has started or is ongoing (no clinical trial registry or news released so far).
Figure 9. Sites of action of diverse molecules being explored for the treatment of achondroplasia.
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| Note that both CNP and meclozine work on the MAPK pathway (RAS-RAF-MEK-ERK). A31 and NF449 are anti-FGFR3 TKIs no longer (to our knowledge) being explored. P3 is a peptide with high affinity for FGFR3 and would have an effect similar to an antibody, but there have been no new publications about it to date (to our knowledge). Source: Matsushita M et al. (2013). Reproduced here for educational purposes only. |
And finally...
Statins
Statins are a group of drugs that are mainly used to lower cholesterol levels in individuals with known high risk of cardiovascular disease (CVD) or those who already had cardiovascular events (14,15). Individuals with familial hypercholesterolemia, including children 8+ years of age, are considered at higher risk of CVD and for this reason statin therapy is also recommended for this group (15).
Notwithstanding, it is interesting to know that statins have been also used in children and adolescents with several disorders in which the goal is not to lower cholesterol levels. For instance, statins have been used to increase (!) cholesterol levels in a genetic disorder called Smith-Lemli-Opitz syndrome which causes impairment on the cholesterol synthesis (16). Other disorders in which statins have also been used in young individuals include pre-eclampsia (in pregnant women) (17), a genetic form of polycystic kidney disease (18), sickle cell anemia (19), a progeria syndrome (20), autism (21) and in neurofibromatosis type 1 (NF1), an autism-related disorder (22-26).
Safety aspects of statin therapy in children
There is an universal question about the risks of using statins in children, because cholesterol is the backbone molecule for many important biological agents (e.g.: several hormones) that drive normal body development.
There is already consensus about the use of statins in children who have high cholesterol levels as this may protect them from future CVD but, what about using statins in children with normal cholesterol levels? The basic question is: what is the risk for a growing child if we reduce cholesterol levels too much ?
Furthermore, as long term statin use has been linked to increased risk of onset of type 2 diabetes mellitus (DM2) in adults, there is also concern about the risk of long term statin therapy on the development of DM2 in the pediatric population, specially in children who do not have high cholesterol levels (27; weak evidence).
To address some of these important questions, safety aspects have been thoroughly examined in several studies performed in children with hypercholesterolemia 8+ years of age (pre-pubertal and pubertal). In these studies (most short/medium term studies) no harmful effects of statins on growth or body development were identified (28,29). However, there are at least two studies following young patients for up to four years showing that there were no harmful effects caused by statins in terms of growth or development (20,30).
We saw that statins have been used in other clinical indications in children, adolescents and pregnant women and reports do not describe any adverse events or undue harm in this population. Because of the expected effect of statins in lowering cholesterol levels, in all these trials researchers kept an eye on the lipid profile of the study participants. In all studies referred above cholesterol levels did drop, but there was no reported case of cholesterol falling off the normal range (17-26).
In summary, although there is still need to check if there are long term negative consequences due to chronic use of statins in children, at the same time there have been no evidence that chronic use of statins will/would cause harm in this population.
Statins and the RASopathies
As we saw above, one of the disorders where statins have been used is NF1, one of the RASopathies. The few veteran visitors of this blog will possibly remember that we have already reviewed the RASopathies here, a group of genetic disorders that are characterized by mutations in enzymes that regulate the MAPK pathway (is this not exactly the main signaling pathway used by FGFR3?). The name says it all: RAS is the first enzyme in the MAPK pathway (FIgure 6). In that article we reviewed an interesting work where researchers used a CNP analogue no longer being explored called NC-2 to reduce the signaling through the MAPK pathway in a model of neurofibromatosis (31).
The theory behind the use of statins in NF1 is that these drugs could help improve learning and behavioral abilities due to their effects in some enzymes, such as Ras, that are thought to drive the impairment in cognitive functions in NF1.
Statins in achondroplasia
You might have also already checked out this blog's previous article published in 2014 where we reviewed a compelling study showing that statins were able to promote bone growth in achondroplasia, although the exact mechanism to explain the effect was not fully elucidated (32). Wait a minute, but we just said that statins can control the MAPK pathway, didn't we?
Statins were further investigated by the group of Dr. Pavel Krejci in 2017, but they found that these drugs did not block FGFR3 signaling, although their models would only partially reproduce a FGFR3-bone dysplasia model (33). Therefore, the question remains about how statins promoted bone growth in achondroplasia in the study by Yamashita and cols (32).
The study of statins in Noonan Syndrome, a RASopathy
We may find some clues to answer this question based on the findings of this interesting study that drove me to write this article, where researchers addressed whether statins would be useful to treat the growth retardation found in Noonan Syndrome (NS), another RASopathy (1).
In NS, an enzyme called SHP2 suffered a mutation and became hyperactive. SHP2 modulates the activity of several other enzymes, including Ras and ERK, which are part of the MAPK pathway (1). The mutant SHP2 increase the activity of the MAPK pathway and this causes bone growth impairment in NS, among other abnormalities.
Tajan and coworkers (1) performed a series of tests in chondrocytes expressing a NS-causing SHP2 mutant and observed that the mutation in SHP2 made the MAPK pathway more active, which in turn leaded to a reduced hypertrophic zone in the growth plates of NS mice compared with normal (wild type, WT) mice. Importantly, they observed that this inhibitory effect was more pronounced in the early or pre-hypertophic zone (Figure 2), which is one of the growth plate zones where FGFR3 is more active (3).
To test if the MAPK pathway was overactive in NS chondrocytes, they used a MEK inhibitor called U126 (MEK is the upstream enzyme that activates ERK), which restored the size of the hypertrophic zone in the growth plate. You can learn more about studies with drugs designed to block the MAPK pathway here. The same results were obtained when they used rosuvastatin, the same statin used by the group who explored the use of statins in achondroplasia (32).
In other words, the study by Tajan e cols. (1) is the second one exploring the use of a statin to restore bone growth by reducing the activity one of the most important enzyme pathways for FGFR3 signaling in chondrocytes.
Since that there is already sound (but not complete) evidence explaining statin's mechanism of action in the growth plate, and that the current safety evidence does not point to specific development harm to exposed children under prolonged statin use, I think that there is ground for pursuing clinical studies with statins in children with achondroplasia.
Researchers looking forward to therapeutic solutions for achondroplasia might find interesting that in an old study with statins in children with hypercholesterolemia, where one of the safety aspects was participants' development, there was a slight increase in height in children exposed to the statin compared to those on placebo (34, cited by 1; just check the population characteristics' table).
Statins would not accumulate over a couple of days. In almost all cases adverse events related to their use were temporary, without permanent sequelae. Statins are low cost oral drugs. Researchers developing statins in clinical settings for achondroplasia would have several established biomarkers to check safety and treatment response. What are they waiting for?
References
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3. Ornitz DM and Legeai-Mallet L. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 2017;246(4):291-309.
4. Wojtal D et al. Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders. Am J Hum Genet 2016;98(1):90-101.
5. Garcia S et al. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.Sci Transl Med 2013;5(203):203ra124.
6. Jin L et al. Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain. Mol Ther. 2016 Nov;24(11):1974-86.
7. Qing J et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest 2009;119(5):1216-29.
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Thank you for a well presented article!
ReplyDeleteOut of curiosity - what could be a safe dosage of statins for a prolonged use for a 2 year old?
This would need to be discussed in an appropriate forum! This author does not recommend starting the use of any therapy without the necessary evidence that it works and is safe! :)
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