[Free Full Text] 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. Among them is an achondroplasia therapy using anti-FGF2 aptamers from Tokyo-based Ribomic.  

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 "€œforming 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

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) and two high molecular weight isoforms (hmw, 21 and 22 kDa). FGF2lmw is secreted (released to the outside of the cell) 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. Which 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, which is about to enter the Toxicological Good Laboratory Practices.

In Ribomic

Fibroblast growth factor 2 (FGF2) is involved in bone growth homeostasis, 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:

"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