Genetic and Molecular Mechanisms of Achondroplasia Offer Novel Treatment Paths

By Kate Knab

A collaborative team of researchers is uncovering mechanisms acting upstream and downstream of the fibroblast growth factor receptor 3 (FGFR3) gene to identify novel strategies to treat achondroplasia and possibly other skeletal malformation disorders.

“Our study suggests for the first time that through genetic targeting of FGFR3 … complications that characterize achondroplasia have the potential to be avoided,” said lead investigator Véronique Lefebvre, PhD.

The Lefebvre Laboratory, along with researchers from Jefferson University and Drexel University, are focusing on basic science approaches to better understand the gene whose alteration in achondroplasia prominently impedes skeletal growth.

“I believe this work could be very important not only for people with achondroplasia but also for people with many other skeletal malformation disorders that result in shortening of all or subsets of bones,” Dr. Lefebvre said.

From development in the womb through puberty, the growth of our bones is driven by cells located in bone tissue templates called cartilage growth plates, where they actively proliferate and enlarge in a process called hypertrophy before being replaced by definitive bone. The gene FGFR3 is a crucial regulator of this process, keeping the proliferation and hypertrophy of these cells in check, lest they cause overgrowth.

Achondroplasia, a genetic condition caused by a mutation that increases the activity of FGFR3 and therefore inhibits bone growth, is the most prevalent type of short stature disorder. While patients can undergo bone-lengthening surgeries or be treated with certain drugs to stimulate growth, Dr. Lefebvre works to inform novel genetic and drug approaches.

These approaches could address not only the growth issue in this disorder, but also neurological issues, such as spine compression due to the narrowing and shortening of the vertebral column and disfiguration due to small craniofacial skeletal elements.

Uncovering ‘Proof of Principle’

Through their grant supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Dr. Lefebvre and her research team published results in the Journal of Clinical Investigation from a study that analyzed the effects of reducing FGFR3 expression in the growth plate cartilage cells of preclinical animal models. Upon searching for the DNA sequences that regulate the expression of the FGFR3 gene, they located -29E as a key driver of FGFR3 expression in cartilage cells.

Working with the Transgenic Core at CHOP, researchers utilized CRISPR/Cas9 technology to create a genetic deletion of -29E in animal models both with and without the FGFR3 achondroplasia variant. The deletion reduced FGFR3 gene expression by half in the growth plate cartilages of all bones.

The -29E deletion did not affect models without the achondroplasia variant. Remarkably, however, disease models with the achondroplasia mutation demonstrated largely normalized growth of all bones, without any adverse side effects.

In addition to lengthening of craniofacial, vertebral and limb bones, researchers also saw significant resolution of the spinal canal stenosis defect, which is what commonly causes painful and occasionally lethal compression of the spinal cord in patients with achondroplasia. As a result of these improvements, researchers noted that the disease models demonstrated a lively, normal lifespan.

“Our study is a great example of proof of principle,” explained Dr. Lefebvre, who is the study’s senior author. “Whereas most pharmaceutical treatments target molecular pathways downstream of the mutant, overactive FGFR3 protein, our study demonstrates for the first time that by targeting the mechanisms that control the expression of the FGFR3 gene, thus before it produces a mutant protein, the skeletal defects and neurological complications that characterize achondroplasia have the potential to be avoided.”

After reporting improvement in the disease models from just a partial reduction of FGFR3 expression, researchers will investigate targeting other sequences around and within the gene to determine if anything stronger than a partial reduction can be achieved.

Molecular Pathway Offers More Insights

Another aim of Dr. Lefebvre’s grant is to expand on preliminary findings that uncovered a link between the FGFR3 variant and a major molecular pathway that regulates the activities of growth plate cartilage cells. Collaborating with Douglas Wallace, PhD, and the Center for Mitochondrial and Epigenomic Medicine, and with researchers at Jefferson and Drexel, the Lefebvre team wants to understand how the mutant receptor might perturb this pathway in the cartilage cells. Next, they will work to identify drugs that could restore normalcy of this pathway.

Dr. Lefebvre is keeping both genetic and pharmacological approaches in mind while she pursues preclinical studies, as patients with achondroplasia currently lack fully satisfying treatment options. A combination of both types of treatments could provide positive outcomes.

Although her focus is on achondroplasia, Dr. Lefebvre anticipates her findings could offer more insights into other chondrodysplasias — disorders that affect a person’s stature and overall health — and could also offer novel treatments for these conditions.

“Everything that we find there, whether it's the approach, how we target the cartilage cells or how we change expression of genes, could, in principle, be applicable to many other skeletal and non-skeletal disorders,” Dr. Lefebvre said.