Both GABA and NMDA systems contribute significantly to regulating CNS function. However, dysfunction in these two systems is known to be at the core of numerous neurological disorders. Navigating these complex circuits is a challenge, but a welcome opportunity for the teams at Sage as we seek to provide new treatments for patients.
We are using our unique development approach to systemically evaluate our drug candidates in a range of neurological, neurodegenerative, and neurodevelopment disorders:
- Anti-NMDA receptor encephalitis
- Essential tremor
- Parkinson’s disease
- Dementia/disorders of cognition
- Huntington’s disease
- Cerebrosterol deficit disorders/Smith-Lemli-Opitz syndrome
Epilepsy is a group of neurological disorders characterized by recurrent seizures (a sudden surge of electrical activity in the brain). Despite there being more than 25 approved therapies for epilepsy, about 30% of patients still suffer from refractory (resistant to treatment) seizures. Imbalance with the inhibitory and excitatory pathways in the brain contributes to the frequency and length of seizures. We’re exploring how enhancing GABA or NMDA signaling could potentially help these patients.
Anti-NMDA receptor encephalitis is a severe neurological condition caused by high levels of antibodies against the NMDA receptor. These antibodies block NMDA receptors and reduce activity in brain circuits. Early symptoms include fever and headache, which can rapidly transition into psychosis, agitation, trouble thinking, seizures, and trouble breathing. Our investigational compound SAGE-718 can enhance NMDA receptor activity and could potentially counteract the neurological effects of the anti-NMDA antibodies.
Essential tremor is the most common movement disorder − 8 times more prevalent than Parkinson’s disease. It is a progressive, often inherited, condition that causes rhythmic trembling of the hands, head, voice, or legs. Researchers think it may be caused by electrical fluctuations in the brain that send abnormal signals out to the muscles. For millions of people, essential tremor makes the simplest activities of daily life difficult, if not impossible. Tremors usually worsen with stress, fatigue and stimulant use. Essential tremor has been associated with reduction in GABA receptor activity.
Parkinson’s disease is a chronic and progressive movement disorder that affects approximately 700,000 people in the U.S. In this disease, nerve cells in the brain slowly stop producing dopamine, the neurotransmitter responsible for coordinating movement. As Parkinson’s disease progresses, dopamine produced in the brain decreases, leaving patients less able to direct their movement. Parkinson’s disease may cause tremors, stiffness, slow movement and balance trouble, as well as mood changes and sleep difficulties. Current treatments for Parkinson’s disease focus on dopamine replacement, and are effective in reducing symptoms initially, but lose effectiveness over time.
GABA receptors may be a possible therapeutic target in the treatment of Parkinson’s disease. GABA signaling is known to help regulate the nerve cells that produce dopamine. Researchers have also found decreased levels of allopregnanolone, a naturally-occurring GABA modulator, in patients with Parkinson’s disease.
Dementia, including Alzheimer’s disease and a broad spectrum of other forms, affects more than 36 million people worldwide. This neurodegenerative disorder is characterized by a decline in cognitive function. Evidence suggests that enhancing the excitatory NMDA pathway in the brain could work to treat several kinds of dementia. Researchers have found elevated anti-NMDA antibodies in many dementia patients.
Huntington’s disease is a rare, progressive, inherited neurodegenerative disease with more than 30,000 diagnosed patients in the U.S. Symptoms appear typically at ages 30–45 and progress over 15–20 years, leading to death in all cases. Huntington’s disease is associated with lower levels of cerebrosterol, a natural positive modulator of NMDA receptor activity.
Cerebrosterol is a natural molecule that acts in the brain to enhance NMDA receptor activity. Several neurodevelopment genetic disorders that affect cholesterol metabolism, like Smith-Lemli-Opitz syndrome, are also associated with lower than normal levels of cerebrosterol. Lower activity of the NMDA pathway could explain the intellectual disabilities and behavior problems associated with these disorders, and suggests a potential therapeutic target.