Beyond Achondroplasia

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RBM 007 – new approach for achondroplasia


The following news was presented in March 2016  by Fierspharma:

Japan’s Agency for Medical Research and Development (AMED) named 8 projects for a pre-designation review as orphan drug commercialization candidates. These include achondroplasia therapy using anti-FGF2 aptamers from Tokyo-based Ribomic.  

An orphan drug is a pharmaceutical agent that has been developed 
specifically to treat a rare medical condition, known as a rare disease. 
Achondroplasia is considered a rare disease."Rare disease" is a 
concept used to identify a medical condition, syndrome, disease or 
disorder that affects less than 5 people in 10.000 (or less than 1 
in 2000) in the European Community or in the USA, less than 
200.000 Americans.
The average ACH prevalence in the world is 1 in 20.000 people

Before going further,  some concepts must be clarified:


What are nucleic acids?

The nucleic acids were discovered in 1868 by Friedrich Miescher, who called the material ‘nuclein’ since it was found in the nucleus of the cells. Dahm R. “Friedrich Miescher and the discovery of DNA“, 2005. Later, it was discovered that the RNA exists also outside the nucleus. DNA can be organized in very large molecules containing millions of nucleotides. For instance, the DNA in the largest human chromosome, the number 1, consists of approximately 220 million base pairs (pairs of nucleotides in the two DNA strands bonded together, more information below) and would be 85 mm long if straightened. Gregory SG, Barlow KF, McLay KE, Kaul R, Swarbreck D, Dunham A, et al. (2006). “The DNA sequence and biological annotation of human chromosome 1“. Nature. 441 (7091):31521


Credits: Nirmala Josephine, “Chemical composition of the cell“, 2014


The nucleic acid RNA is a copy of the sequence of the gene information contained in the DNA and functions as a mold in composing the proteins in a living body. But in addition to being a copy of the gene information, RNA has an important role in “forming various three dimensional structures”. It is a copy of the genetic information in the DNA and serves as a means of transportation of this information from the nucleus to the cytoplasm, where it will be interpreted. It can also have regulatory, transport and enzymatic roles in the cell.

What is an oligonucleotide?

Oligo means a very small number. Each nucleotide is a building block for the nucleic acids: DNA and RNA. DNA exists as double-stranded molecules and RNA as single-stranded molecules.

Signaling in bone development

Various signaling molecules control the process of skeleton development, such as the fibroblast growth factor (FGF), the wingless-type MMTV integration site family members (Wnt) and the bone morphogenetic protein (BMP) signaling pathways. Among these signaling pathways, FGF/fibroblast growth factor receptor (FGFRs) signaling is highly essential. Su N. et al.  Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models

boneres20143-f1 (1)

The blue lines mean that those molecules inhibit the parts of chondrocyte development they “point” to and the red arrow means that that stage of development is promoted. Image credits: Nan Su, Min Jin & Lin Chen 2014

  • FGF2 is one of the earliest members identified in the FGF polypeptide family, and is expressed in the majority of cells and tissues including the limb bud, chondrocytes and osteoblasts. FGF2 is stored in the extracellular matrix (outside the cells).
  • FGF2 has three isoforms: a low molecular weight isoform (lmw, 18 kDa – kDa is a molecular weight measure) and two high molecular weight isoforms (hmw, 21 and 22 kDa). FGF2lmw is secreted (produced) and activates FGFRs (meaning that it binds to FGFRs).
  • Studies indicate that FGF2 isoforms have important effects on bone homeostasis and different FGF2 isoforms perform distinct roles. Su et al.

A number of anti-FGF2 monoclonal antibodies (mAbs) have previously been developed and shown to neutralize various activities of FGF2 in vitro and in some cases in vivo. However, to our knowledge, no anti-FGF2 mAb has been entered into clinical trials. Jin el at. Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain

What is an aptamer?

Aptamers are small single-stranded DNA or RNA oligonucleotide fragments or small peptides that can bind to targets with high affinity and specificity. Aptamers are specific, non-immunogenic (do not trigger immune reactions) and non-toxic (do not damage the organism).

Imagine that the aptamer is like a magnet. And that it only binds
specifically to one single type of particle. Once the aptamer binds
to the particle, blocks its activity and the particle is eliminated
by the immune system.

Aptamers work outside the cells, unlike other nucleic acid drugs that, in order to execute their function, have to go inside of cells. And this represents a great challenge.

Category Basic structure Target Mechanism
Aptamer Single stranded RNA/DNA protein Inhibits the physiological effect
Aptamers are applicable to therapeutics by strong and specific neutralizing activities, and hold several pharmaceutical advantages compared to antibodies such as:
  • medium size between antibodies and small molecules
  • chemical synthesis
  • production cost
  • little antigenicity

Jin el at. Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain


RBM 007: anti-FGF2 aptamer

Ribomic is a Japanese biotechnology company working with aptamers for innovative therapeutics.

In Ribomic pipeline there are several aptamers and among them is RBM 007, under investigation for 5 conditions incluiding ACH, twhich is about to enter the Toxicological Good Laboratory Practices.

GLP - Good Laboratory Practices
International regulations that must be observed to ensure high
quality, experimental standards and reliable data. In EUPATI.

Fibroblast growth factor 2 (FGF2) is involved in bone growth homeostasis (healthy balance), absorption and regeneration and its up-regulated imbalance is known to cause bone destruction diseases often associated with severe pain. Although there are several drugs available to prevent or cure inflammation associated with bone diseases, there is a limited number of drugs primarily for bone destruction disorders.

An aptamer that blocks the FGF2 is an anti-FGF2 aptamer. This means that the aptamer binds with the FGF2 (that is the target molecule) preventing it from binding to FGFR3.

Original article by Ribomic researchers:

Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain, Jin L. et al. 2016

“Fibroblast growth factor 2 (FGF2) plays a crucial role in bone remodeling and disease progression. However, the potential of FGF2 antagonists for treatment of patients with bone diseases has not yet been explored. We therefore generated a novel RNA aptamer, APT-F2, specific for human FGF2 and characterized its properties in vitro and in vivo. APT-F2 blocked binding of FGF2 to each of its four cellular receptors, inhibited FGF2-induced downstream signaling and cells proliferation, and restored osteoblast differentiation blocked by FGF2.

APT-F2P, a PEGylated form of APT-F2, effectively blocked the bone disruption in mouse and rat models of arthritis and osteoporosis. Treatment with APT-F2P also exerted a strong analgesic effect, equivalent to morphine, in a mouse model of bone cancer pain. These findings demonstrated dual therapeutic action of APT-F2P in bone diseases and pain, providing a promising approach to the treatment of bone diseases”.

At AdisInsight, there is the following information on RMB 007
  • Originator – Ribomic
  • Class – Peptide aptamers
  • Mechanism of Action – Fibroblast growth factor inhibitors
  • Orphan Drug Status – No
  • On Fast track – No
  • New Molecular Entity – Yes
Highest Development Phases
  • Preclinical – Achondroplasia; Age-related macular degeneration; Bone disorders; Cancer pain
  • Research – Fibrosis

Most Recent Events

  • 21 Jul 2016 – Preclinical trials in Achondroplasia in Japan (unspecified route)


Aptamers are an innovative branch of research and the RMB 007 can show interesting results for bone diseases and seem to have a high potential of sucess as therapeutical agents. Meanwhile, RMB 007 is under study for several conditions at the same time which is not ideal. It seems that Ribomic is testing in which condition this aptamer will show better results and will only keep the best results in the pipeline. Nevertheless, lets wait to see what follows if RMB 007 passes the GLP stage for ACH.

Special Thank you to Eihaku Itooka, from “Glory to Achondroplasia” for sharing the information on RMB 007


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