SCIENCE & TECHNOLOGY
Receptor editing – which was initially described in immunology – is a regulation mechanism of key receptors (e.g. 5HT2cR, AMPAR) involved in brain diseases (such as depression, schizophrenia or neurodegenerative diseases) or in the mechanism of action of pharmacological agents (such as an antidepressant or anti-obesity drugs).
Biocortech has developed the only technology enabling a complete, precise, reliable and scalable measurement of editing profile, i.e. the distribution of isoforms of an edited receptor.
Generalities
Editing is a recently discovered mechanism and a topic of increasing interest in the scientific community
Formally defined as an RNA-processing event, occurring upstream to splicing, editing results in RNA transcript with a primary nucleotide sequence, which is different from the one expected from its coding gene sequence.
The editing process occurs through a variety of modifications consisting in deleting, inserting or substituting nucleotides . The latter one, substituting editing is the most commonly identified type of editing in mammals (in contrast to lower organisms), usually represented by a direct nucleotide modification.
As for alternative splicing, RNA editing is a mechanism through which several isoforms of a protein can be synthesized from one given gene.
Relevance of editing
Several proteins of major medical and pharmacological interest, e.g. ApoB, proteins of GPCR family (e.g. 5HT2c receptor), or channel receptor (e.g. AMPA receptor) are edited.
Receptor editing mediates a functional regulation of receptors. Changes on editing sites at RNA transcript level are mirrored by changes of the structure of the synthesized protein. Such structural changes may turn into functional alteration (e.g. alteration of the binding between 5HT2cR and its G protein).
Contrary to mutated DNA, which stays unaltered all the life long and can be used as a biological marker to identify patients at high risk for developing a disease (genetic predisposition profiling), edited RNA varies according to physiological or disease state, or pharmacological intervention.
The form of editing primarily considered by Biocortech is A to I editing
This form of editing consists in the substitution of A by I on specific sites (‘editing sites’) of RNA. There are five editing sites on 5HT2cR RNA.
A to I editing is controlled by ADAR (adenosine deaminase acting on RNA), an enzyme that forms a dimer on (double-stranded) RNA
Relevance of A to I editing
Key receptor proteins are A to I edited: 5HT2cR (serotonin), AMPAR (glutamate), CRP, cGMP receptor
A to I receptor editing mediates a functional regulation of edited receptors since editing sites correspond to sites of the corresponding synthesized protein that are involved in the receptor function (for instance, edited sites of 5HT2cR RNA correspond to 5HT2cR protein sites involved in its binding with the coupled G protein).
Development of A to I editing-related clinically relevant or pharmacological applications was impeded by the lack of way to measure all edited isoforms at once.
Editing profiling
Editing profiling consists in measuring mRNA expression of all isoforms in the considered sample at once (i.e. in one experiment) and in displaying the distribution curve of quantities of isoforms.
Displayed editing profiles can be seen as ‘barecode- like’ signatures of editing activity corresponding to disease states such as depression or drug neurological safety/toxicology effects.
For purpose of diagnostic and translational research applications, editing profiles are thus informatically processed in order to quantify it and to infer expression level of a proprietary blood circulating 5HT2cR editing-related biomarker.
Relevance of 5HT2cR editing
Serotonin 5HT2c receptors play an important role in the modulation of monoaminergic transmission, mood, motor behavior, appetite and endocrine secretion and 5HT2c sites are involved in the actions of several classes of antidepressants.
Alterations of the functional status of 5HT2c have been detected in anxiodepressive states and more specifically, correlation between expression of 5HT2cR RNA edited isoforms in specific brain cells and suicide has been established by renown academic groups.
Correlation of 5HT2cR editing with disease states such as depression and with drug neurological safety/toxicology effects underpin the possibility to base new and very promising approaches to diagnose, treat and monitor patients suffering from depression (MDD) upon 5HT2cR RNA editing-related applications.
Biocortech 5HT2cR editing technology platform
Biocortech operationalized the platform with respect to serotonin receptor (5HT2c)
and proved the concept of a blood test of depression /suicide by:
- evidencing specific alteration of 5HT2cR edition in suicide patients as compared to non suicide patients
- identifying blood circulating biomarkers of 5HT2cR edition (patented)