Life science
Medical & healthcare, Drug development

Development of oligonucleotide aptamer therapy forachondroplasiaLife science

Department of Pediatrics, Graduate School of Medicine
Assistant Professor Takeshi Kimura

https://researchmap.jp/kimutake

Associate Professor Takuo Kubota

https://researchmap.jp/k_b_t

Professor Keiichi Ozono

https://researchmap.jp/read0092357

Abstract
Achondroplasia (ACH) is the most prevalent genetic form ofdwarfism in humans, caused by activating mutation in FGFR3 tyrosine kinase. The clinical need for safe and effective inhibitor ofFGFR3 is currently unmet, leaving ACH an incurable condition. Weevaluated the RBM-007, a RNA aptamer developed to neutralize
the FGFR3 cognate ligand, FGF2, for its activity against FGFR3 signaling in cartilage. In cultured chondrocytes and in cartilage xenografts derived from ACH-iPS cells, RBM-007 rescued the proliferation arrest and aberrant chondrocyte differentiation and maturationin the growth plate cartilage. When delivered by subcutaneousinjection, RBM-007 restored defective bone growth in mouse modelto ACH.

▍ Background & Results
Achondroplasia (ACH) is the most common dwarfism in humans,
occurring in 1: 25,000 live births. ACH is caused by mutations in
the FGFR3 gene, which encodes a transmembrane receptor tyrosine kinase. No therapy exists for ACH except for growth hormone,
which is approved for ACH in Japan and shows limited effect. Although several experimental approaches for targeting FGFR3 arebeing tested, including small chemical inhibitors of FGFR3 catalytic
activity or biomolecules targeting downstream pathways of FGFR3
signaling, there is no definitive therapy for ACH.
In this study, a RNA aptamer named RBM-007 are examined as
potential drug for ACH. Aptamers are short RNA or single-stranded
DNA oligonucleotides that can bind to their targets like antibodies
and are functionally used as antagonists, agonists, or targeting
ligands. RBM-007 can bind human FGF2 specifically and does notaffect other FGFs.
We show that neutralization of FGF2 ligand by RNA aptamer
RBM-007 restores defective bone growth in FGFR3-related skeletal
dysplasia in mice. RBM-007 inhibited activation of FGFR3 signaling
in cultured chondrocytes in vitro as well as in tibia organ culturesand cartilage xenografts differentiated from hiPSCs derived fromindividuals with ACH. More importantly, when administered to mice,the RBM-007 restored defective skeletal growth in the ACH model.

▍ Significance of the research and Future perspective

Figure1: The mechanism of RNA aptamer
RBM-007 is composed of 36 nucleotides and binds stably and specifically toFGF2 but not to the other FGFs. RBM-007 confirmed the blocking effect in FGF2
binding to human FGFR3 and suppress signaling pathway induced by FGF2.

Figure2: Drug discovery process in our research
In addition to traditional in vitro and in vivo tests using animal model, we evaluated the efficacy of RBM-007 with patient-specific hiPSC models. The clinical trial
program for RBM-007 in ACH treatment have been initiated in Japan.

We demonstrate an approach to target FGFR3 signaling in skeletal dysplasia based on a ligand-trap concept. RBM-007 could
potentially be used for full restoration of skeletal growth in patientswith ACH, although this remains to be tested in future studies.
RBM-007 is already undergoing a clinical evaluation in the United States (NCT03633084 and NCT04200248), and a clinical trial
program for ACH treatment was initiated in Japan in July 2020
(JapicCTI-205345).

P a t e n t
Kimura, Takeshi; Bosakova, Michaela; Nonaka, Yosuke et al.
T r e a t i s e An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice.
Sci Transl Med. 2021 May 5;13(592):eaba4226. doi: 10.1126/scitranslmed.aba4226
URL
K e y w o r d achondroplasia, RNA aptamer, patient-specific iPS cells