small molecule - big impact
Our lead candidate, MIC-083, is based on an
innovative microRNA approach for the
treatment of major depression disorder and
treatment resistant depression – areas with
significant unmet needs
Studies demonstrate microRNA-135 levels are
significantly reduced in the brains of suicide
victims and in the blood of depressed patients.
Thus, the therapeutic strategy for the MIC-083
program consists of replenishing endogenous
Overwhelming data demonstrate a direct involvement of microRNA-135 in depression and anxiety models. It impacts several key genes associated with neuropsychiatric disorders, and has the potential to modulate an entire biological pathway that is disrupted in depressed patients.
Dual activity for treatment
- 5-Hydroxytryptamine Receptor 1A (HTR1A) has a dual and opposite effect in depression and anxiety depending on location: suppression of HTR1A autoreceptors located in presynaptic neurons in the dorsal raphe nucleus (DRN) enhances stress resilience/antidepressant response; whereas, reductions in post-synaptic HTR1A heteroreceptors are associated with depression and anxiety.
- Depressed patients and suicide victims show increased levels of presynaptic HTR1A autoreceptors which correlate with resistance to treatment with antidepressant drugs.
- The widely common HTR1A rs6295 polymorphism has been associated with increased levels of the presynaptic autoreceptors, leading to depression, suicide and SSRI resistance.
- Reduction in serotonin transporter (SERT) levels following SSRI treatment produces an increase in extracellular free serotonin 5-hydroxytryptamine (5-HT) , that activates HTR1A autoreceptors which in turn reduce neuronal firing – a mechanism that is proposed to underlying treatment resistant depression (TRD).
- MIC-083 is a single therapy that hits both targets and– unlike other agents- avoids inhibition of post-synaptic heterorecpetor HTR1A and instead specifically targets presynaptic neurons. This dual effect makes MIC-083 a promising therapy for TRD.
In a rodent model, administration of a proprietary siRNA conjugated to sertraline (the ligand) was compared to
intraperitoneal fluoxetine (an SSRI) treatment. Serotonin levels in brain dialysate rose earlier and more rapidly
following treatment with the siRNA conjugate as compared to fluoxetine
Unique dual mechanism of action
- Unlike SSRIs, MIC-083 doesn’t block the serotonin
transporter (SERT). Instead, it reduces SERT expression
levels by 50%.
- MIC-083 also reduces 5-HT1A autoreceptor expression,
which may overcome the delayed onset of action usually
observed with SSRI treatment.