Therapeutics for Epilepsy and other Neurological Disorders

Description:

The inventors discovered a novel non-toxic agent that attenuates seizure activity in two animal models of epilepsy. This agent is a highly potent Vitamin K analogue that was first identified in a chemical screen using a zebrafish model of epilepsy (Figure 1). This agent was further tested in several mouse models of epilepsy, performed at the NIH Anticonvulsant Screening Program. The preliminary tests showed that this compound was protective in the minimal clonic seizure (6 Hz) and the corneal kindled mouse models (Table 1 & 2). This agent also protected HT-22 neuronal cells from glutamate excitotoxicity by preventing programmed cell death associated with oxidative stress in neurons and oligodendrocytes. These results indicate that this novel agent could be used to treat neurodegenerative diseases such as epilepsy, Parkinson’s disease, and traumatic brain injury.

 

 

Overview: Each year, over 300,000 people in the United States die from neurological injuries and diseases, with direct health care costs exceeding $220 billion per year. Many neurological diseases have underlying mitochondrial dysfunction, with increased oxidative stress and cell death. There are no effective treatments for many neurological diseases. In particular, epilepsy is a debilitating disease affecting 1-2% of the world’s population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by the current available medications; thus there is a critical need for new anti-seizure drugs.  Development of therapeutics that prevents seizures and neuronal cell death would lower health care costs, improve quality of life, and lower the rates of morbidity and mortality.

 

Advantages: This novel agent is a small and potent Vitamin K analogue.  In both zebrafish and mouse models of epilepsy, this agent is effective without requiring any special formulations. Levels of Vitamin K synthase and Vitamin K have recently been identified as negative enhancers for Parkinson’s disease; our novel agent may have therapeutic potential for other neurological diseases.  Our data suggests that our Vitamin K analogue is likely working to protect mitochondria and could additionally be useful for patients with mitochondrial diseases. In addition, no toxicity was observed in mice at high doses (>100 mg/kg). This indicates good therapeutic tolerance, which is highly desirable for patients with compromised health status.

 

Key Words: Epilepsy, Parkinson’s, stroke, traumatic brain injury, Alzheimer’s, Huntington’s, and Amytrophic Lateral Sclerosis, HT22, glutamate toxicity, cell death, acute neurological diseases, chronic neurological diseases, neurons, oligodendrocytes

 

Publications: Rahn, J. J., et al. "Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy." Neuroscience 259 (2014): 142-154.

 

Josey, Benjamin J., et al. "Structure–activity relationship study of vitamin k derivatives yields highly potent neuroprotective agents." Journal of medicinal chemistry 56.3 (2013): 1007-1022.

 

Inks, Elizabeth S., et al. "A novel class of small molecule inhibitors of HDAC6." ACS Chemical Biology 7.2 (2011): 331-339.

 

Inventors: C. James Chou, Sherine S. Chan, Jennifer J. Rahn, Benjamin J. Josey

Patent Status: US Utility Application 14/440,155 Filed 11/11/2013

MUSC-FRD Technology ID: P1225

 

Licensing Status: Licensed to MUSC startup, Neuroene. Please contact FRD for additional information or to be put in touch with Neuroene.

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
hankinsm@musc.edu
Inventors:
Chung-Jen (James) Chou
Sherine Chan
Jennifer Rahn
Benjamin Josey
Keywords:
neurological
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