TECHNOLOGY

Glutamate is the most abundant excitatory neurotransmitter in vertebrate sensory systems and the brain. Upon synaptic release, glutamate activates metabotropic glutamate receptors (mGluRs) as well as ionotropic receptors (NMDA, AMPA and kainate receptors).

MGluRs are class C G-protein coupled receptors (GPCRs) with widespread expression in the mammalian nervous system. As such, mGluRs are involved in many neural processes regulating important physiological and pathological processes.

mGlu7 receptor and PTSD

The involvement of excess levels of glutamate in brain damage produced by stress has not received sufficient attention. Stress can induce profound increases in brain levels of glutamate, a neurotransmitter which is involved in memory and anxiety, and in the production of the traumatic memory, as well as the emotional components of PTSD.

The mGlu7 receptor is specifically located in these brain regions that regulate anxiety, memory and emotion, and has been shown to act as a key tuner of imbalanced glutamate levels associated to trauma-related brain mechanisms.

PRAGMA’s technology is based on the allosteric modulation of the mGlu7 receptor which corresponds to a unique and innovative approach to regulate stress-related responses, fear and cognitive dysfunctions associated to PTSD.

Specifically acting in brain regions altered by the trauma, PRAGMA’s lead molecule has demonstrated efficacy in a proof-of-concept study, alleviating stress behavior in a translational animal model of PTSD. PRAGMA is now further progressing its molecules into additional studies, supported by brain imaging (i.e., PET tracer and receptor occupancy) and biomarkers identification.

Some references:
Myers KM et al. (2011) Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Neuropsychopharmacology Reviews, 36, 274.
Popoli M et al. (2012) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nature Review Neuroscience, 13:22.
Singewald N, et al. (2015) Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther, 149:150.
O’Connor RM et al. (2010) Metabotropic glutamate receptor 7: at the interface of cognition and emotion. Eur J Pharmacol, 639(1-3):123.
O’Connor RM et al. (2013) Adult siRNA-induced knockdown of mGlu7 receptors reduces anxiety in the mouse. Neuropharmacology, 72:66.
Gee CE, et al. (2014) Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior. J Biol Chem, 289(16):10975.

mGlu7 receptor and Hearing Loss

Glutamate is also the primary excitatory neurotransmitter of both the inner ear (peripheral auditory system) and parts of the brain used for hearing (central auditory system). Recent findings indicate that cochlear synaptic mechanisms involving glutamate excitotoxicity can contribute to hearing impairments from a similar event.

Protection against glutamate insults may provide therapeutic solutions to the degeneration of the synaptic contacts between inner hair cells and spiral ganglion neurons, frequently implicated in the pathogenesis of sensorineural hearing loss (SNHL) caused by various factors, such as noise overexposure and aging.

Interestingly, the mGlu7 receptor is expressed in hair cells (HCs) and in spiral ganglion neurons (SGN) of the inner ear as well as at the auditory nerve fibre synapse in the mammalian cochlea in human, which comprises a key part of the pathway from the inner ear to the brain necessary for normal hearing.

More importantly, three Genome-Wide Association Studies (GWAS) confirmed the unique and critical role of the gene encoding mGlu7 receptor (GRM7), strongly linked to age-related hearing loss in American, European, and chinese populations. By dampening glutamate neurotransmission and excitotoxicity through the application of an mGlu7 allosteric modulator, we anticipate a major improvement of auditory functions, protecting and/or preventing damage of the hair cells and auditory nerve fibers against glutamate excitotoxicity insults.

Some references:
Myers KM et al. (2011) Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Neuropsychopharmacology Reviews, 36, 274.
Nordang L et al, (2000) Acta Otolaryngol; 120(3):359-62.
Friedman RA et al. (2009) GRM7 variants confer susceptibility to age-related hearing impairment. Hum Mol Genet; 18(4):785-96.
Newman DN et al. (2012) GRM7 variants associated with age-related hearing loss based on auditory perception. Hear Res; 294(1-2):125-32.
Luo H et al. (2013) Association of GRM7 variants with different phenotype patterns of age-related hearing impairment in an elderly male Han Chinese population. PLoS One; 8(10):e77153.
Lu Y (2014) Metabotropic glutamate receptors in auditory processing. Neuroscience; 274:429-45.