Therapeutic Areas
We are creating a portfolio of region-selective compounds for ionotropic glutamate receptor-mediated disorders, starting with PTSD.
Post-Traumatic Stress Disorder (PTSD) is an incapacitating mental health condition that develops after exposure to a traumatic event with long-lasting, debilitating symptoms like flash-backs and hyper-reactivity. About 8-10% of Americans—over 25M people—are living with PTSD, from abuse, accidents, and natural disasters. Under normal circumstances, behaviors associated with PTSD are adaptive for coping with the trauma. For instance, avoiding stimuli associated with the traumatic event lessens the probability of encountering the threat or others like it. However, patients with PTSD lose normal daily functioning because these responses become dysfunctional and exaggerated. PTSD is also closely tied to homelessness, substance abuse, and a staggering suicide rate.
Post-Traumatic Stress Disorder
The current diagnostic standard is administering subjective symptom checklists long after the trauma. The ambiguity surrounding these checklists leads to underdiagnosis and misdiagnosis, and these checklists certainly do not inform treatment. Existing medications are also not effective—they either mask select symptoms or they are illicit with unknown mechanisms of action. Read Why Not Other Drugs?
Clinicians do the best with the tools they have, but existing tools are not good enough. There is a massive opportunity to bring relief to millions of people if we just start focusing on the actual science…and we’re doing just that.
Scientific Rationale
An overactive amygdala, the brain’s fear center, is one of the hallmarks of PTSD and is responsible for disease pathology. Human and preclinical studies have long shown that trauma causes high activity in the amygdala. While surgical intervention to balance amygdalar activity have proven successful for the most severe cases, no approved or experimental PTSD medications directly target amygdala hyperactivity.
The research underlying the current PTSD investigations at Neurovation Labs utilized a robust model of PTSD in rodents called stress-enhanced fear learning (SEFL). In the SEFL model, an acute, severe, and unpredictable stressor permanently sensitizes subsequent conditional fear learning. The procedure is likened to a PTSD trigger, like a car backfiring, setting off a disproportionate fear reaction in a patient suffering from PTSD. Such a reaction is the crux of PTSD symptomatology and is captured in the SEFL rodent model along with the other PTSD symptoms identified in the DSM-V checklist.
SEFL is a unique PTSD model in that it combines multiple behavioral techniques. Because of this, we can truly capture all aspects of the disorder, including exaggerated or sensitized fear, blunted emotional reactivity, dysregulated HPA axis activation, anxiety and depressive behaviors, as well as increased consumption of alcohol.
Dr. Perusini together with Dr. Fanselow found that after a traumatic experience, there are long-term increases in calcium-permeable, ionotropic glutamate receptors in the amygdala. These receptors are the neurophysiological correlate of activity after a learning event. The result of the persistent increase is the observation that we always see in those suffering from PTSD: an overactive amygdala. This regional receptor increase provides an exceptional target for therapeutic intervention. Neurovation Labs is building on these discoveries to develop a treatment that focuses on the physiological cause of PTSD, as well as a companion diagnostic to determine those who would benefit from the treatment.
Traumatic Brain Injury
Traumatic Brain Injury (TBI) is a debilitating brain dysfunction that plagues active duty military and veterans, occurring after a physical injury such as a blast or an accident. Mild TBI (mTBI) results in similar brain dysfunction after single or repeated exposure to more mild traumas, such as the concussive forces that mortmen experience. Over 350,000 diagnoses of TBI have been made in the U.S. military since 2000. Among those deployed, estimated rates of TBI range from 11–23%. Beyond the military, TBI imposes an economic burden exceeding $76 billion. Immediate or delayed physical TBI symptoms may involve confusion, blurry vision, and concentration difficulty. The long-term psychiatric and neurological consequences of TBI include dementia, epilepsy, and suicidal ideation.
Establishment of universal and comprehensive TBI assessment and treatment protocols has been a challenging healthcare hurdle, largely due to the condition’s heterogeneous nature, the vast range of symptomatology, and the scope of severity. The FDA has not yet cleared or approved any standalone medical products that are intended specifically to diagnose or treat TBI, including concussions. Like other brain disorders, TBI is currently diagnosed using symptom checklists like the Glasgow Coma Scale (GCS) and clinical neurological tests to determine dysfunction in motor skills, speech, cognition, and reflexes. Imaging modalities, such as computerized tomography (CT) or magnetic resonance imaging (MRI), cannot be used to diagnose TBI because they lack sufficient sensitivity to detect the subtle abnormalities that characterize mTBI; they are only employed to rule out severe or life-threatening injury that requires immediate or surgical attention (i.e., bleeding near the injury site).
Current medications only treat immediate and indirect consequences, such as over-the-counter NSAIDS for headache, diuretics for reduced tissue fluid, anti-epileptic medications to prevent epilepsy, and in severe cases, coma-inducing medication. These diagnostic and treatment regimens for TBI and mTBI are either untenable, perform poorly, or offer very little relief for patients.
Scientific Rationale
As in PTSD, glutamate signaling also underlies TBI pathology. Injury causes glutamate to be released indiscriminately, which may also change GluA1-containing AMPA receptor composition. These receptor modifications render glutamate profoundly more toxic to injured neurons than healthy tissue, leading to excitotoxicity and cell death commonly associated with TBI. This is because excitotoxicity is a pathological consequence of prolonged activation of glutamate receptors; the hyperactivity results in excessive calcium influx into the cell, eventually leading to cell death. Oligodendrocytes, the cells that make up the myelin sheath around the axon (i.e., the part of the brain cell necessary for communication), contain these GluA1-containing receptors, rendering them potentially vulnerable to excitotoxicity; the consequence of this is long-term and irreversible brain damage resulting from TBI. The difference between using increased GluA1 as a biomarker for PTSD versus TBI lies in the brain region in which GluA1 is increased: increased amygdalar GluA1 indicates PTSD, while increased GluA1 near a brain injury site (usually cortical) indicates early, developing TBI. Therefore, GluA1 may serve as an excellent brain biomarker to diagnose TBI or mTBI, predict disease severity, differentiate between the two conditions, and allow for intervention before long-term damage sets in.