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 22nd July 2020

These are active times for the Japanese company RIBOMIC, announcing on the 30th June that the outline of Phase I study of RBM-007 (an anti-FGF2 aptamer) for treatment of Achondroplasia has been registered and published in JapicCTI, the Japanese clinical trials agency (read the registration of the CT here)  and on the 15th July, announced that the first adult healthy volunteer was administered subcutaneously with RBM-007 in a Phase 1 Clinical Trial for the treatment of Achondroplasia.
In April 2020, we published news the New drug application for achondroplasia by RIBOMIC which can be read here.
Yet, some years have passed since the first time we referred to RBM-007 and aptamers for the treatment of achondroplasia. Was back in Sep 2016 that a first post was published in the previous Beyond Achondroplasia blog, that can be read here. RBM-007 is an aptamer, an innovative molecule, which is currently under phase 2 trial in the United States for the treatment of age-related macular degeneration.

What is an aptamer?

An aptamer is a sequence of single-strand nucleic acid (DNA or RNA) with a variable region of about 40 nucleotide bases. This variable sequence confers each aptamer with a unique 3-dimensional structure and potential ligand-binding capability.  These factors make aptamers high affinity and specific binding molecules, able to differentiate between targets that differ by only one functional group. It is because of this that aptamers are often called ‘nucleic acid antibodies’. Aptamer/target binding is achieved mainly through electrostatic interactions, so the variability in aptamer sequences is what gives them their versatility. The way aptamers fold, the order of the nucleic acids, and the conditions of the matrix they are in, all contribute to binding a target.

3 aptamers 1

Figure 1. Aptamer structures are binding to small and large target molecules. Credits: Aptamer Group

A paper from Nakamura Y, 2017 explains what these molecules are and how they work: "The therapeutic molecules can be classified as low-, middle- and high-molecular-weight drugs depending on their molecular masses. Antibodies represent high-molecular-weight drugs and their clinical applications have been developing rapidly. Aptamers, on the other hand, are middle-molecular weight molecules that are short, single-stranded nucleic acid sequences that are selected in vitro from large oligonucleotide libraries based on their high affinity to a target molecule. Hence, aptamers can be thought of as a nucleic acid analog to antibodies."

What is the connection for the RMB-007 aptamer to achondroplasia?

In achondroplasia, a dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor receptor 3 (FGFR3) and its downstream mitogen-activated protein kinase (MAPK) signaling pathway. This inhibits chondrocyte differentiation and puts a brake on growth plate function, in addition to causing serious medical complications such as foramen magnum and spinal stenosis and upper airway narrowing. Hogler W & Hard L, 2020

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 (the target molecule) preventing it from binding to FGFR3.

string hires image

                                                                                                         Figure 2. Connections of FGFR3 with ligands. Credits: String

The Phase 1 clinical trial will undergo until May 2021, as announced by the company. New information regarding the next phase (phase 2 in children) can be expected in early 2021.

Nakamura Y, 2017 Aptamers as therapeutic middle molecules
RIBOMIC press release 30th June
RIBOMIC Press release
 15th July

What is an aptamer - Aptamer Group
Hogler W & Hard L, 2020 - New developments in the management of achondroplasia
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