Treating achondroplasia with meclizine / meclozine

Before starting

Sometimes, for the non-technical readers it might be difficult to copy with the language used in articles like this one. If you start to feel like a bit lost in the jargon, don't give up. This blog contains many other articles which have been written with the goal of sharing knowledge while simplifying the language of the science behind the bone growth biology and achondroplasia. Try to visit the index in your preferred language on top of this page. The first articles present the basics in a more digestible way (at least, I tried to make it so) and may help you to follow the more recent ones.
 
Introduction

Following the publication in 2013 of the exciting study about the use of meclizine to treat achondroplasia (1; reviewed here), the Japanese group leaded by Matsushita has just published the results from their continuing exploration of the use of this compound to treat this bone growth disorder. The conclusions of this study will help to define the next steps for meclizine in this new therapeutic indication: could it be used in the clinical settings, i.e., can it be tested in children with achondroplasia? So, let's see what the researchers found in their study and think about their results and potential next steps.

Old dog, new trick

Repurposing or repositioning of old drugs is a strategy more and more recognized as a viable way to find therapies for new indications across the vast existing drug armament. The goal is to help reducing the ever increasing costs of drug development by using medicines that have their mode of action and safety profile already established and are approved for the market, thus reducing the development burden. A drug falling in this category could proceed to clinical testing for a new indication in far lesser time than that needed for a new molecular entity (this is the way the regulatory agencies such as the FDA call a brand new compound).

Interested in achondroplasia, in 2103 Matsushita and coworkers published the article (1) where they describe that they screened among almost 1200 old compounds from a FDA approved list available for drug repositioning, for one which could be used to treat this skeletal dysplasia, and identified meclizine as a candidate. 

Meclizine, or meclozine, (Figure 1) pertains to the large familiy of anti-histamine drugs and is an old medicine currently indicated for motion sickness.

Figure 1. Molecular structure of meclizine.

From Wikipedia

In that study, they tested meclizine in mice bone explants and found that the drug was capable to partially restore the bone growth by reducing the activity of one of the main chemical cascades fibroblast growth factor receptor 3 (FGFR3) uses to exert its effects in the growth plate chondrocyte, the mitogen activated protein kinase (MAPK) pathway (Figure 2). As you may already know, FGFR3 acts as natural negative modulator (a brake) in the bone growth machinery and due to the mutation found in achondroplasia, it becomes much more active, leading to bone growth arrest. The MAPK cascade (or pathway) includes the enzymes RAS, RAF, MEK and ERK (and others), which are activated (ignited) in sequence by FGFR3, like in a domino chain.

Figure 2. Meclizine site of action.

Matsushita M et al. (2013). PLoS ONE 8(12): e81569. doi:10.1371/journal.pone.0081569.
 Reproduced here for education purposes only.

What is new?

In the current study, they made new tests, this time exploring the effects of meclizine in a mouse model of achondroplasia. In summary, they verified that meclizine did exert a positive effect in bone growth, making the mutated animals treated with this drug to grow more compared with those animals not treated. However, the amount of the effect, although statistically significant, can't be classified as a full growth rescue.

Meclizine was administered in doses equivalent to the therapeutic doses used to treat motion sickness in humans. This means that the effect was observed in doses that would be unlikely to be toxic for children with achondroplasia.

They treated animals carrying the mutation from the third week of life, when part of the cranial bones have already achieved its final development. I refer here to the cranial bone sutures. These parts of the cranium close earlier in achondroplasia than in the average child, leading to potential clinical complications and to some of the typical head features seen in this genetic condition. They found that the therapy with meclizine couldn't rescue the growth pattern of the cranial bones, confirming one of the findings of another important study recently published. (3) 

This has key implications about the timing to start the therapy for achondroplasia. Since FGFR3 is already causing growth disturb in utero the sooner a therapy for achondroplasia could start the better. Theoretically, this would be important for all bones to allow a better development, but would be indeed more relevant for the bones of the head. So, as part of the investigation, the authors also gave meclizine to pregnant wild type (not affected by the mutation) animals. They found that the offspring of these animals grew more than the those from animals not given the drug. The authors didn't describe if there was any sign of toxicity with the use of meclizine neither in the pregnant females nor in the offspring. However, the observed results warrant the tests in affected animals, which they state they will be doing in the next step of their research.

In summary, these are the major findings in the new study by Matsushita et al.:

• Mice carrying the achondroplasia mutation grew significantly more when exposed to meclizine;
• The effect was observed specially in long bones. The cranial bones have not responded to the therapy;
• The bone growth effect was significant but didn't restore in full the expected bone growth;
• The effect in bone growth was obtained with doses considered achievable in the therapeutic range;
• The effect in bone growth was also observed in normal animals.

More food for thoughts 
(see the review about statins, recently published)

The unveiling of some old drugs that may have a role in the therapy for achondroplasia is fantastic. If proven to work in its known therapeutic dose range (in other words, to be safe and efficient in usual doses) meclizine might represent one major achievement for the treatment of achondroplasia, having at least three key advantages against new compounds in development right now:

1. It is readily and easily available worldwide;
2. It is cheap;
3. It is an oral drug.

Nevertheless, it is good to keep a realistic view about the research with meclizine performed so far. Although several tests are still in the line before assuming any effect in children with achondroplasia at any degree, given the current results, it looks like it will not be able to rescue the full potential growth in affected individuals.

This open the option of associating drugs which also have the potential to beat the mutated FGFR3, specially if they have distinct modes of action. This is exactly the case of the statins, which have been recently showed in another study to promote bone growth in achondroplasia. Combining these drugs may result in a synergistic effect, while keeping the drugs in their safe dosing range.

Another aspect is that they could also be combined with other therapies in research right now. For instance, in theory meclizine could be used with C-type natriuretic peptide (CNP) analogues, antibodies or other compounds targeting FGFR3. 

And finally 

As I have been pointing out in previous articles, one major concern about new therapies for any medical condition is about how they will be made available for the individuals in need after they are approved by the regulatory authorities. A number of recent analyses made by the specialized press have been showing that clinical development is becoming more and more expensive in the last decades, strongly pushing higher and higher the costs of the medicine in the consumer end. This is reality for common diseases such as diabetes or hypertension. This is indeed even more serious issue for rare conditions.

On the other hand, this poses a challenge to drug developers. How they will make the new drug useful if few can afford to pay the price? A rational agreement must be found among all the stakeholders involved, from the drug makers, the health authorities, to the interested population and their representatives.

Therefore, (re)discovering meclizine and other compounds may represent good options and fair argument over excesses we might see in the future with the arrival of newly developed compounds. In the end of the day, balance between the industry sustainability speech (and the deserved reward for the good discovery job) and fulfilling the very one goal of any new therapy - to treat those in need - is much desired.
 
References

1. Matsushita M et al. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS ONE 2013 8(12): e81569. doi:10.1371/journal.pone.0081569. Free access.

2. Matsushita M et al. Meclozine Promotes Longitudinal Skeletal Growth in Transgenic Mice with Achondroplasia Carrying a Gain-of-Function Mutation in the FGFR3 Gene. Endocrinology 2014 Dec 2:en20141914. [Epub ahead of print]. Free access.

3. Matsushita T et al. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 2009;18(2):227-40. Free access.

Treating achondroplasia with statins

Introduction

Nature, one of the most renowned scientific journals of the world, has published a compelling study performed by a Japanese group, in which these researchers investigate the use of statins for the treatment of achondroplasia. (1)

Statins are a family of drugs widely used to reduce blood cholesterol levels, with the goal of reducing the risk of an individual to have a cardiac attack or to have another attack in the future. However, statins have been shown to have several other potential therapeutic effects in a number of different situations, from preventing excessive scarring in healing processes to positive effects in animal disease models such as Alzheimer dementia. (2)

Another aspect of statins is that they have been shown to exert anti-proliferative actions in cancer cell models, with some investigators suggesting that they could be included as "add-ons" in the treatment of malignant diseases (3).

Nevertheless, the reason why the Japanese group chose statins to be tested in their mutant fibroblast growth factor receptor 3 (FGFR3) / achondroplasia model was the finding that statins have been shown to ameliorate osteoarthritis, likely to have positive effects in chondrocytes.(4)

However, before taking a look in this interesting work by Yamashita and coworkers, in respect to the eventual new readers, let's just point out some concepts about FGFR3 and its mode of action, so to make it easier to understand the topic. 

FGFR3 and cell proliferation

If you have read past articles published in this blog you probably know that FGFR3 is an agent that usually promotes cell growth and proliferation. The relevant exception is exactly the chondrocyte living in the growth plate, in which FGFR3 works as a natural growth brake. In achondroplasia, FGFR3 has its structure altered (mutated) and this change makes it more active than normal, thus increasing the brake potency. The result is well known: long bones grow significantly less than expected and other bone structures are affected as well. It is noteworthy that regardless of the cell or tissue, FGFR3 uses the same chemical signaling cascades to exert its effects. The difference is not in the FGFR3 mode of action itself, but in the cell where it is working.

We could think in a chemical/signaling cascade or pathway as a domino chain (Figure 1).

Figure 1. Starting a chain reaction.

The finger (a FGF) taps the first block (FGFR3) and in sequence, it takes down the second, which in turn does the same with the third one till the last one of the row. Figure 2 depicts the main chemical cascades inside the cell that respond to the activation of FGFR3. The letters you see in the figure are acronyms for several reactive proteins (or enzymes) interacting one another to send the signal to the cell nucleus. These chemical cascades are amazing in the sense that what is going on is simply the transfer of electric charges from one molecule to another. How they know what to do with them is something to think about (they don't have GPS, do they?). You can find more about this topic in other articles of the blog.

Figure 2. FGFR3 main signaling cascades (MAPK, PI3K-AKT and JAK-STAT).

As mentioned above, in all cells, when FGFR3 is activated (turned on, or electrically charged) it will trigger the cascades shown in Figure 2, which will take the electric charge to the cell nucleus, which in turn will respond with other chemical reactions making the cell multiply. The exception is the chondrocyte living inside the cartilage growth plate, in which the opposite happens, when FGFR3 is activated, the nucleus responds by stopping the proliferation machinery.

Now, watch this 14 min illustrative animation provided by Cold Spring Harbor Laboratory, to see how a signaling cascade might work in the molecular level:

DNA Learning Center by Cold Spring Harbor Laboratory

FGFR3 has already been recognized as one of the growth agents used by some kinds of cancer to help malignant cells to proliferate. As noted above, these cells take advantage of the chemical pathways activated by FGFR3, such as the mitogen activated protein kinase cascade (MAPK (RAS-RAF-MEK-ERK); Figure 2). (5)

Controlling the signal

FGFR3 is only one of the many growth stimulators present in the cell surface. You might remember from another article here, FGFR3 is like an antenna in the roof of the cell, waiting for the appropriate signals carried by FGFs to transmit the message to the nucleus: "grow". There are many other growth triggers and you can imagine what would happen if all of them were working non stop. Cells and tissues would grow indefinitely causing a lot of problems. Grossly speaking, cancer is like this, the ill cells lose their control systems, or disable them, and start to proliferate at will. 

Then, how is this growth control obtained in the normal cell, preventing a cell to freak out?

In the same way there are many growth inducers (think positive), there are also growth inhibitors (the negative), other molecules the body produces to balance the positive ones. Each cell is prepared to stop the activity of an activated enzyme, through some, let's say janitor systems. When a protein like FGFR3 is activated, not only it attracts the next one in its classic chemical cascade (e.g.: MAPK), but also will call the attention of others that exist to knock down its activity. These clearing systems bind to the activated molecule and either make it inactive again by dispersing the electric charge (recycle) or simply by degrading it.

So, this seems to be the link between statins and FGFR3 seen in the exciting work by Yamashita et al.: it looks like the statins tested were capable to drive the chondrocyte janitor system towards the activated FGFR3, causing its faster degradation. 

Well, how could this help us in achondroplasia? The FGFR3 mutation that causes achondroplasia not only makes the enzyme more active but also make it active for longer. In the study by Yamashita et al., the statins were able to attenuate the effects of the mutation by leading FGFR3 to degradation through one of the cell janitors called proteasome pathway.

Statins under the spotlight

The work by Yamashita et al. has at least one major breakthrough in terms of scientific advance. Instead of performing their main tests only in animal cells, which is easier, they used human stem cells derived from tissue from donors bearing tanatophoric dysplasia type 1 (TD1) and achondroplasia mutations. You might remember that there are other activating mutations identified in FGFR3 causing more or less severe clinical features. TD1 is one the most severe syndromes linked to FGFR3 mutations.

The researchers also prepared normal human stem cells to behave like chondrocytes and in some of them they implanted an altered FGFR3 bearing the achondroplasia mutation (the others were used as controls, to allow comparisons). These cells presented disfunctions similar to the ones we see in real achondroplastic chondrocytes. When exposed to statins these altered cells showed improvement in their chemical activities and growth, reacting closer to what the comparative normal cells did. Furthermore, the stem cells derived from TD1 and achondroplasia were exposed to statins and had their disfunction diminished.

The authors also tested a statin, rosuvastatin (RSV), in a mouse model of achondroplasia, and found significant improvement in growth of some of the bones more affected by the mutation (Figure 3).

Figure 3. Effects of exposure to rosuvastatin in wild type (control) and achondroplasia like mice.

Nature

513,

507–511

(25 September 2014)

doi:10.1038/nature1377

5. Reproduced here for educational purposes only. 

Pay attention to the graphics. The P value on the right describes the significance of the differences seen with the exposure to the drug. In this article, a P less than 0.05 was considered significant, so numbers with more zeros mean that the drug made difference, compared to the affected animal not exposed. We can see that in all comparisons, the affected animals treated with RSV grew more than the affected animals not treated (first P value). It is also showed that there were no differences between the control animals exposed and not exposed (third P value). The second P values stands for the comparison between the effect of the exposure to the treatment in the achondroplasia animal with the non treated control animal. Some of the comparisons were not significant meaning that the bone length of the treated animal was comparable to the bone length of the non treated control animal. 

Statins for achondroplasia ?

The authors ended up by proposing that statins could be used in therapy for achondroplasia, pending learning which statin, or statins, would be more adequate for children, and the right doses as well. Having being in the market for decades, the safety profile of statins is very well known, although data on its risk profile in children is still scarce. In their study, they treated the animals with a dose which is comparable to the largest dose used in the real life to treat high cholesterol levels in adult humans and, at this dose, the risk of liver, renal and muscle toxicity is higher. 

In this context, there are some genetic and inflammatory conditions, such as systemic lupus erithematosus and familial hypercholesterolemia, that lead to high cholesterol levels in children, and in consequence increasing the risk of cardiovascular complications early in life. These conditions have been treated with statins and to assess the safety of this drug family in these groups, Researchers have been publishing a number of studies, reviews and analyses.(6-8) Although the doses used in these studies were lower than the doses used by Yamashita and coworkers in their work, the reported safety outcomes are reassuring: so far there have been reported only rare serious adverse events in the children population treated with statins.

Pros and cons

Let's see what other experts in the area have commented about the study by Yamashita et al. In the News and Views section of the same Nature issue where the work by the Japanese group was published, Olsen (9) commented that the results shown might lead one to think on the use of statins to treat achondroplasia, but that extreme care should be taken in consideration to keep the appropriate level of cholesterol in children taking these drugs.

In an article published in the online version of The Scientist, Yandell (10) interviewed some of the experts in the field. One of them, Laurence Legeai-Mallet (INSERM Institute, Paris), who participated in some of the studies performed with BMN-111, the CNP analogue now in clinical trials, noted that the bone growth effect was not dramatic, and that the animal model used showed only a mild phenotype (the achondroplasia characteristics). Dr Andrea Superti-Furga, from the University of Lausanne, one of the great world authorities in skeletal dysplasias, mentioned that the work was a wonderful proof of concept of the use of statins for the treatment of achondroplasia, but it also raised a lot of questions. You can find out more about these and other scientists on the right side of the blog page, clicking on their respective links.

Finally, it seems that statins could be used to treat achondroplasia, provided the right steps were taken before, to understand how it really works in the growth plate cartilage, what is the actual intensity of the effect and what would be the implications for other aspects of the child health with its use in large doses for a long period of time. For instance, lowering too much the cholesterol levels with a statin in a child could be harmful for his/her development.

This is not the end

A great aspect of this study is the rescue of an old family of drugs to repurpose it for a new clinical indication. The same has been done with meclizine, a drug used for motion sickness which has been shown to promote bone growth in an achondroplasia model in another recent study. (10)

Two major key advantages of these "old" drugs are that their safety profiles are largely known, and their costs are low. This, in turn, brings another challenge to the stage. To perform all the research needed to allow a drug to be commercially prescribed, the researcher must fulfill an enormous volume of tests, from verifying the reproducibility of the results, understanding the drug mechanism of action, checking its toxicity, to most crucial of all, performing tests in the affected individuals to prove the therapeutic concept. This is a very expensive path to be pursued and a huge challenge to be beaten when there is no patent protecting the drug and, in consequence, the investment needed. For a common disease these challenges would be already hard, but for rare conditions the barrier is indeed taller. Who would invest millions to prove that an old drug without patent could treat achondroplasia or similar rare conditions? To let you have another view of this topic, I invite you to read this short article by Dr Nicolas Sireau, the head of the Alkaptonuria Society, a physician and father of two kids with alkaptonuria, and one of the most combative leaders in favor of rare diseases (thank you Ines, from Beyond Achondroplasia). 

Finally, while a recent study by the Tufts CSDD stated that a new drug could cost up to USD 2.6 billion, the Doctors Without Borders (Medecins Sans Frontiers) contests these figures saying that a drug could be developed at far lower costs, let's say the costs of 4 or 5 top soccer/football players in Europe. 

Food for thoughts

There are some doubts about the capacity of statins to significantly rescue the bone growth in achondroplasia. It seems that a large dose would be necessary to see results, which brings the questioning about risks. But, what if the dose needed to promote FGFR3 degradation was not that large? Could the statins be combined with other drugs, such as meclizine, found to be potentially therapeutic in achondroplasia to rescue bone growth? In such a combination, there would be a drug inhibiting the MAPK cascade (meclizine) while the other would be accelerating the FGFR3 degradation. Two different mechanisms of action to reduce the FGFR3 signaling to promote bone growth. Could this also allow for lower doses of both drugs? To answer all these and many other questions, research must be performed first.


References

1. Yamashita A et al. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature (17 September 2014) | doi:10.1038/nature13775.

2. Barone E et al. Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets. Biochem Pharmacol 2014; 88(4): 605-16.

3. Pisanti S et al. Novel prospects of statins as therapeutic agents in cancer. Pharmacol Res 2014 Oct;88:84-98. doi: 10.1016/j.phrs.2014.06.013. Epub 2014 Jul 5.

4. Yudoh K, Karasawa R. Statin prevents chondrocyte aging and degeneration of articular cartilage in osteoarthritis (OA). Aging (Albany NY). 2010 Dec;2(12):990-8. Free access.

5. Feng S et al. Fibroblast growth factor receptors: multifactorial contributors to tumor initiation and progression. Histol Histopathol (2014) 29: 000-000. Free access.

6. Schanberg LE et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents.Arthritis Rheum 2012;64(1):285-96. Free access.

7. Vuorio A et al. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev. 2014 Jul 23;7:CD006401. Free access.

8. Kusters DM et al. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA. 2014;312(10):1055-7. 

9. Olsen BR. Disease models: Statins give bone growth a boost. Nature 2014; 513: 494–5.

10. Yandell K. Statins Stimulate Bone Growth? The Scientist 2014. Free access.

11. Matsushita M et al. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One 2013; 8(12):e81569. doi: 10.1371/journal.pone.0081569. Free access.