Lauren Witty

10/23/21
Individual Project 1: Adding to the Scaffold of the OER

The More You Know: Current Research on Curing and Mitigating the Effects of Achondroplasia

Achondroplasia: Constant Fibroblast Growth Factor (FGF) Signal Due to Mutation in FGF Receptor 3
(FGFR3)

Depending on how much detail is provided in the chapter about FGF and Achondroplasia, add this
background section:

Background: Fibroblast Growth Factor has a permissive action that signals the differentiation of
chondrocytes (cartilage cells) into new bone. Normally, FGF is regulated over time as chondrocytes
need time to expand in order to develop into a normal adult skeleton. However, in patients with
achondroplasia, the FGF receptor is constantly activated, due to a missense mutation, leading to
overactivity of the MAPK pathway, and the inhibition of chondrocyte proliferation and differentiation
in the growth plate. This leads to less bone elongation and a skeleton of shorter stature.

Make sure that chapter has this basic information about achondroplasia as well as its common
impacts/co-morbidities

Is there a cure for Achondroplasia?

Currently, there is no cure for achondroplasia. Over 80% of cases of achondroplasia occur due to a
missense mutation, and are not the result of hereditary inheritance patterns. The other 20% of cases are
due to inheritance, as achondroplasia follows an autosomal dominant inheritance pattern.1 Since
achondroplasia is largely due to genetic mutations, and no gene therapy has been developed to treat it,
there is no available cure.

However, in recent years, researchers have been working to develop treatments that can restore bone
growth in achondroplasia patients. Here is some of the current literature surrounding treating
achondroplasia:

1. sFGFR3 Therapy: sFGFR3 is a soluble form of human FGFR3 that serves as a decoy
receptor. When injecting sFGFR3 into an achondroplasia patient, sFGFR3 will prevent FGF
from binding to the mutant receptor, as it instead binds to sFGFR3. This interrupts the FGF
signaling cascade, causing increased differentiation of chondrocytes, and has restored normal
bone growth in recent studies.

While this therapy has not been used in humans, the researchers studying this concept have
found promising results. After repeated subcutaneous injections, mice with achondroplasia
have exhibited normal bone growth over time. This study also identified improvements in

1
“About Achondroplasia.” Genome.gov, National Human Genome Research Institute, 15 July 2016,
https://www.genome.gov/Genetic-Disorders/Achondroplasia.
 reproduction availability, as the pelvis was able to fully form.2 Expanding on this research, the
drug Recifercept is currently in clinical development, and if approved, will serve as an FGFR3
decoy and restore normal bone growth within patients with achondroplasia.3 However, the
commercial use of this drug will not likely begin for a while, as it has to go through testing
with minors, it’s target population. This approval process is more rigorous and faces additional
ethical barriers than drugs approved for adults, so it is unlikely that Receifercept will be
approved for at least a few more years.

2. C-type Natriuretic Peptide (CNP) Analog: Another receptor, Natriuretic Peptide Receptor
Type B (NPR-B), also exists on the plasma membrane and has the ability to inhibit the MAPK
pathway. When the MAPK pathway is inhibited, chondrocytes are able to proliferate and
differentiate, leading to normal bone development. NPR-B is stimulated by a C-type Natriuretic
Peptide, so current research projects are looking at the addition of a CNP Analog in
achondroplasia patients and its impact on their bone development.4 Vosoritide (BMN111) is a
CNP analog that is currently in clinical development. Mouse models treated with Vosoritide
showed a significant recovery of bone growth and an improvement in dwarfism-related clinical
features.5 And in 2019, there was a research study to determine the effectiveness of this drug in
children with achondroplasia. After a single subcutaneous injection per day for 6 months, the
researchers found an increase in annualized bone growth velocity. However, Vosoritide caused
adverse effects in all participants, and adverse events in some, which signals that more research
needs to be conducted.6

3. Statin Approach: Statins are a largely utilized drug that lead to a decrease in cholesterol and
low-density lipoprotein concentrations within the body. While mostly used to lower cholesterol
and provide protection from a heart attack or a stroke, statins also have other abilities. In 2014,
researchers were curious about the effect of statins on skeletal dysplasia, including
achondroplasia. Before this research, it was known that statins had anabolic effects on
chondrocytes, so researchers hypothesized that statins may be able to help repair damaged
cartilage. Through this experiment, researchers used mevastatin, atorvastatin, pravastatin,
rosuvastatin, and fluvastatin, and found that these statins were able to correct degraded
cartilage. While the exact mechanism behind their ability to restore cartilage is unknown, it is
hypothesized that statin treatment may accelerate the degradation of the mutant FGFR3 protein
in differentiated cells.7

4. Meclozine: Meclozine (aka Meclizine) is an over the counter motion-sickness drug that has
been utilized for over 50 years. However, it has recently been involved in treating
achondroplasia in juveniles. In a 2013 study, it was discovered that Meclozine has the ability to
inhibit the FGFR3 signaling pathway, and therefore upregule the differentiation of
chondrocytes. While active research is still occurring in this field, it is hypothesized that

2
Garcia, Stéphanie et al. “Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.” Science translational medicine vol.
5,203 (2013): 203ra124. doi:10.1126/scitranslmed.3006247
3
Goncalves, Diogo, et al. "In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia." PLoS
ONE, vol. 15, no. 12, 28 Dec. 2020, p. e0244368. Gale Academic OneFile,
link.gale.com/apps/doc/A646874329/AONE?u=wash_main&sid=bookmark-AONE&xid=6c929026. Accessed 26 Oct. 2021.
4
Unger, Sheila et al. “Current Care and Investigational Therapies in Achondroplasia.” Current osteoporosis reports vol. 15,2 (2017): 53-60.
doi:10.1007/s11914-017-0347-2
5
Högler, Wolfgang, and Leanne M Ward. “New developments in the management of achondroplasia.” “Neue Entwicklungen im Management der Achondroplasie.”
Wiener medizinische Wochenschrift (1946) vol. 170,5-6 (2020): 104-111. doi:10.1007/s10354-020-00741-6
6
Savarirayan R, Irving M, Bacino CA, et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019;381(1):25-35.
doi:10.1056/NEJMoa1813446
7
Yamashita, Akihiro, et al. "Statin treatment rescues FGFR3 skeletal dysplasia phenotypes." Nature, vol. 513, no. 7519, 25 Sept. 2014, pp. 507+. Gale Academic
OneFile, link.gale.com/apps/doc/A383856048/AONE?u=wash_main&sid=bookmark-AONE&xid=be4556dc. Accessed 26 Oct. 2021.
 meclozine reduces the phosphorylation of ERK in the MAPK pathway. This leads to a halt in
the MAPK pathway, and therefore an increase in differentiation of chondrocytes.8

Figure 1. This figure illustrates

the pathways in which different
drugs treat achondroplasia. The
normal FGFR3 pathway is
pictured in the bottom left of the
figure, and leads to inhibition of
chondrocyte proliferation and
differentiation. The other 3 visuals
show how sFGFR3, Meclizine and
Vosoritide inhibit the MAPK
pathway and restore chondrocyte
proliferation. Statins are not
pictured in this figure, as they
result in the degradation of
mutant FGFR3 proteins.

What Next?

While an accessible gene therapy treatment for achondroplasia does not seem apparent in the coming
years, treatment options for young achondroplasia patients are numerous and promising. Vosoritide has
shown the most promising results in both mouse and human models and is an accessible option as it
only requires a daily injection. However, this is a field of study that needs to be explored more
thoroughly. Researchers are still trying to understand the full mechanism of FGFR3 and it’s
downstream pathways. Gene therapies are still being researched, in an effort to determine if that is a
plausible way to actually cure achondroplasia.

But, it is also important to remember that achondroplasia only impacts a small subset of people, and
therefore, is not always prioritized. While this opens the door for questions about healthcare and
research equity, it is important to acknowledge the biases that exist within medicine and how those may
impact what treatments to diseases are explored, and which are not.

8
Matsushita, Masaki, et al. "Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated
FGFR3 Signaling in Achondroplasia." PLoS ONE, vol. 8, no. 12, 4 Dec. 2013, p. e81569. Gale Academic OneFile,
link.gale.com/apps/doc/A478431743/AONE?u=wash_main&sid=bookmark-AONE&xid=21e5cea2. Accessed 26 Oct. 2021.
 WORKS CITED

“About Achondroplasia.” Genome.gov, National Human Genome Research Institute, 15 July 2016,
https://www.genome.gov/Genetic-Disorders/Achondroplasia.

Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, Patouraux S, Tran A, Gual P, Le

Marchand-Brustel Y, Gennero I, Gouze E. Postnatal soluble FGFR3 therapy rescues
achondroplasia symptoms and restores bone growth in mice. Sci Transl Med. 2013 Sep
18;5(203):203ra124. doi: 10.1126/scitranslmed.3006247. PMID: 24048522.

Goncalves, Diogo, et al. "In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth
factor receptor 3, as treatment for achondroplasia." PLoS ONE, vol. 15, no. 12, 28 Dec. 2020, p.
e0244368. Gale Academic OneFile,
link.gale.com/apps/doc/A646874329/AONE?u=wash_main&sid=bookmark-AONE&xid=6c9290
26. Accessed 26 Oct. 2021.

Högler, Wolfgang, and Leanne M Ward. “New developments in the management of achondroplasia.”
“Neue Entwicklungen im Management der Achondroplasie.” Wiener medizinische Wochenschrift
(1946) vol. 170,5-6 (2020): 104-111. doi:10.1007/s10354-020-00741-6

Matsushita, Masaki, et al. "Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by

Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia." PLoS ONE, vol. 8, no.
12, 4 Dec. 2013, p. e81569. Gale Academic OneFile,
link.gale.com/apps/doc/A478431743/AONE?u=wash_main&sid=bookmark-AONE&xid=21e5ce
a2. Accessed 26 Oct. 2021.

Savarirayan R, Irving M, Bacino CA, et al. C-Type Natriuretic Peptide Analogue Therapy in Children
with Achondroplasia. N Engl J Med. 2019;381(1):25-35. doi:10.1056/NEJMoa1813446

Unger, S., Bonafé, L. & Gouze, E. Current Care and Investigational Therapies in Achondroplasia. Curr
Osteoporos Rep 15, 53–60 (2017). https://doi.org/10.1007/s11914-017-0347-2

Yamashita, Akihiro, et al. "Statin treatment rescues FGFR3 skeletal dysplasia phenotypes." Nature, vol.
513, no. 7519, 25 Sept. 2014, pp. 507+. Gale Academic OneFile,
link.gale.com/apps/doc/A383856048/AONE?u=wash_main&sid=bookmark-AONE&xid=be4556
dc. Accessed 26 Oct. 2021.