Treating achondroplasia

Article originally published in Spanish, English and Portuguese at Fundación Alpe website www.fundacionalpe.org) in September 2011. This text is out of the sequence started in this blog.


Achondroplasia (ACH) is the most common form of dwarfism, with a case estimate of ~1:15000 to 1:25000 births. It is most commonly the result of a de novo mutation of the fibroblast growth factor receptor 3 (FGFR3).

Mutations in the FGFR3 leading to the ACH family of chondrodysplasias are caused by single substitutions of one aminoacid of the protein chain. In the case of ACH, more than 90% of the carriers bear the G380R substitution in the transmembrane domain of the receptor. FGFR3 is mainly expressed in the proliferative chondrocyte region of the growth plate. This receptor tyrosine kinase has a normal negative action on the bone growth and, because the mutation results in a gain of function, the growth plate chondrocytes have an impaired proliferation rate and are induced for an early terminal differentiation, compared to normal individuals, leading to the typical dwarf phenotype.

A note about the cartilage growth plate. This is an avascular, dense, electrically charged environment, functioning as strong barrier for molecules to reach the chondrocytes. Experiments have shown that free diffusion through the growth plate is easier for compounds with less than 50kDa.

What does already exist in terms of pharmacological approaches against FGFR3?

The best strategy should be that directed specifically against the FGFR3, such as antibodies or the tyrosine kinase inhibitors (TKI), but other options are acceptable. Some of these indirect approaches work counteracting the FGFR3 effects in bone growth, although they do not reduce the mutant receptor activity.

• Antibodies anti-FGFR3 have already been developed and show strong and reliable affinity and specificity to the receptor. The main issue is that most of them are large in size (more than 50 kDa), and some tests already performed showed that the dose needed to achieve a therapeutic effect in ACH mice models was toxic and lethal.

• Several TKIs available to date have have shown activity directly against the FGFR3, however none of them seem to be specific enough to allow further development. Most of these TKIs have also action, for instance, against the vascular endothelial growth factor receptor (VEGFR), another receptor enzyme with important actions. The most recently published promising anti-FGFR3 TKI is the NF-449. The NF-449 seems to be more specific than other TKIs but it is still in basic research.

• Parathyroid Hormone (PTH) plays a main role in bone growth. A PTH related protein, PTHrP, is a bone local key factor responsible for maintaining chondrocytes in the proliferation phase, thus positively and strongly influencing the bone growth. Analogues and other compounds to induce sustained release of PTH are being explored for the treatment of osteoporosis and, until recently, there were groups exploring PTHrP actions in ACH models. Some PTH analogues, like teriparatide, are already being marketed to treat osteoporosis in adults. The Food and Drug Administration (FDA) has posed severe restrictions for the use of teriparatide. For instance, its use is forbidden in children, because teriparatide showed to induce osteosarcoma in rats given extremely high doses of this PTH analogue in a life-long manner. Authorities fear that the anabolic effects of teriparatide could lead to a higher risk of cancer development in young, as children have a natural high metabolic rate and would be more prone for neoplastic transformation. It is important to note that, since its launch, there is no one single report linking teriparatide to osteosarcoma in users.

• Menaquinones, represented mainly by menatetrenone (MK-4), are compounds pertaining to the vitamin K2 family. In Japan, MK-4 is used for the treatment and prevention of osteoporosis and also as an adjuvant treatment in advanced liver cancer. A recent paper showed that it acts by reducing the expression of FGFR3 in hepatocarcinoma cells, thus helping to induce them to programmed cell death (apoptosis). It is possible that the same effect in the expression of FGFR3 could be verified in chondrocytes, however this must be tested.

The recommended dose of MK-4 in osteoporosis is 45mg/day (less than 1mg/kg/day in a 50kg adult). This dose is already far larger than the standard nutritional dose recommended by health authorities around the world.

More recently, a Japanese group, looking at long term effects of the use of high doses of MK-4 in rats, found that those rats fed with MK-4 grew more than the control. However, in this paper, the dose of MK-4 the rats were exposed, 30mg/kg/day, is by far higher than the osteoporosis doses and much more indeed than the nutritional ones. Although MK-4 has an excellent safety profile in the recommended dose for the treatment of osteoporosis, a minority of patients suffers of increase in the liver enzymes. Therefore, until specific tests in ACH are performed to check if it can reduce the expression of FGFR3 and also the safety profile is addressed in larger doses, it is too early to say MK-4 or other menaquinone would have a role in ACH.

• C-type Natriuretic Peptide (CNP) is a natural positive player in chondrocyte proliferation by reducing the progression speed of these cells to a more mature state called hypertrophy. It is locally released and seems to not have significant systemic actions, even in large doses. A group from the University of Kyoto, in association with Chugai, a Japanese pharmaceutical industry, has developed a CNP analogue which is frankly in pre-clinical development in mouse models. It seems to rescue most of the features of the ACH phenotype. The caveat is that they are working with a CNP continuous infusion model and this kind of treatment strategy has several practical limitations. To overcome this potential burden, Biomarin, another industry, is developing another CNP analogue (BMN-111) for daily subcutaneous injections. Preliminary results are promising, and Biomarin plans to apply for clinical trials already in 2012.

In summary, currently, the most promising therapeutic option for ACH is the CNP analogue BMN-111, which is planned to start being tested in humans in 2012. Other potential therapies include the blockage of FGFR3 with specific inhibitors, such as NF-449, and the use of PTH or PTHrP to counteract the effects of FGFR3. MK-4 or other menaquinones, must be tested before they should be considered for ACH, due to the very high pharmacological doses supposed to have an effect in FGFR3.