Translational Activators of the Glutamate Transporter EAAT2 to Treat Neurological and Psychiatric Diseases

Small molecule technology with novel translational activation mechanism.

The Need

Glutamate is a major neurotransmitter in the mammalian central nervous system (CNS) and essential for normal brain function including cognition, memory, and learning. However, the extracellular concentration of glutamate must remain below excitotoxic levels (~ 1 μM) to avoid overstimulation of glutamate receptors, leading to neuronal damage or death. Excitotoxicity has been associated with multiple acute neurological conditions such as ischemic stroke, epilepsy, and trauma, chronic adult-onset neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), and depression. One potential approach to preventing excitotoxicity is to enhance glutamate reuptake. EAAT2 is the major glutamate transporter and functions to remove glutamate from synapses. An increase in EAAT2 protein expression and function can provide a means to prevent insufficient glutamate reuptake and consequently reduce neuronal damage.

The Technology

Drs. Chien-Liang (Glenn) Lin and Kevin Hodgetts have developed a series of compounds that incresse EAAT2 protein expression and their lead compound, LH-1, shows great promise as an Alzheimer's theraputic. In vivo mouse data demostarites that treatimet with LH-1 results in incresed EAAT2 espression in the brians of wildtype mice.

Administering a daily dose LH-1 at a 10mg/kg to a neurodegenerative mouse model, Tau mouse, resulted in a stasititically signaificatnt restoration in congantive function.

Stage of Development

LH-1 has been identified as the lead compound and the inventors have funding from the Alzheimer's Drug Discovery Foundation and have completed GLP toxicology studies. The inventors are submitting an IND application with plans to begin a Phase 1 clinical trial.

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