Amyotrophic Lateral Sclerosis (ALS), also called Lou Gehrig's disease in the United States, is a late-onset, devastating fatal neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the spinal cord, motor cortex and brainstem. The goal of this U01 Blueprint grant is to optimize and develop small molecule activators of EAAT2 glutamate transporter protein expression as a means to treat ALS. EAAT2 expression is highly regulated at the translational level. In collaboration that was started more than 3 years ago with Dr. Lin at Ohio State University, we have identified molecules that increase expression of EAAT2 through a translational mechanism. Increased EAAT2 expression has been shown to compensate for the excessive excitotoxicity from high glutamate levels found in a number of diseases including ALS. The two lead molecules have been shown to cause a dose and time dependent increase in EAAT2 in a primary astrocyte cell line and in mouse spinal cord and brain. These compounds have been optimized to demonstrate proof-of-concept in vivo, but still need to be further optimized to improve potency and pharmacokinetic properties. Pharmacokinetic studies have been completed and acute and chronic maximum tolerated dose studies are in progress to help drive additional medicinal chemistry efforts.

Public Health Relevance

Amyotrophic Lateral Sclerosis (ALS), called Lou Gehrig's disease in the United States, is a late-onset, fatal neurodegenerative disorder characterized by progressive degeneration of motor neurons in the spinal cord, motor cortex and brainstem. The average life expectancy from diagnosis is 3-5 years. The goal of this grant is to further develop compounds into novel therapeutics for ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS074601-02
Application #
8294684
Study Section
Special Emphasis Panel (ZNS1-SRB-E (35))
Program Officer
Cywin, Charles L
Project Start
2011-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$38,918
Indirect Cost
$17,115
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Kong, Qiongman; Chang, Ling-Chu; Takahashi, Kou et al. (2014) Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection. J Clin Invest 124:1255-67
Kong, Qiongman; Takahashi, Kou; Schulte, Delanie et al. (2012) Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus. Neurobiol Dis 47:145-54