David Auerbach, PhD has been awarded over $1 million from the National Institute of Neurological Disorders and Stroke over the next three years. The project aims to develop a research platform for the development and testing of medications that could help reduce and prevent seizures, and thus possibly prevent Sudden Unexpected Death in Epilepsy (SUDEP). SUDEP is the leading cause of death in epilepsy. Auerbach is an Assistant Professor of Pharmacology at Upstate Medical University, and his lab works to advance the understanding of neuro-cardiac electrical disturbances. 

From left to right: Laura Williams (MD/MS Student), Dr. Justin Ryan (Data Analyst), Veronica Singh (PhD student), Dr. David Auerbach (Principal Investigator), and Kyle Wagner (Lab Manager)

Finding safe treatments for epilepsy is critical; people with epilepsy are at a 24-fold higher risk of sudden death. “Oftentimes we focus a lot on the psychosocial comorbidities related to epilepsy; ‘If I have seizures I can't drive, it's hard for me to get to work,’” says Auerbach. “But the scariest point is these people are at a very high risk of sudden death, and to make it even scarier, oftentimes we don't know the underlying cause.”  

Researchers have found that some cases of SUDEP are linked to genetic variations related to heart rhythm problems, specifically Long QT Syndrome (LQTS). “Several years ago, with a large clinical database at the University of Rochester, I showed that there was a link between LQTS and an increased prevalence and risk of seizures,” explains Auerbach. “While we were excited about those results, we didn't understand the mechanism for it.” 

LQTS Type 2 is caused by genetic variants in a gene called KCNH2, which produces a protein called Kv11.1. This protein is important for regulating the electrical activity of the heart and brain. People with LQT2 who also have epilepsy need effective medications to control their seizures. Up until now, there was a lack of animal models that accurately mimic LQTS-related epilepsy for research purposes. 

To address this gap, the researchers are using a gene-editing technique called CRISPR-Cas9 to generate rabbits with a genetic mutation in the KCNH2 gene that mimics the human condition.  

“This grant is going to enable us to first demonstrate that this animal model reproduces the pathologies and abnormalities that are seen in people with this disease, then we can better understand the underlying causes,” says Auerbach. 

He explains that the exact reason for seizures in LQTS isn’t completely understood. “We think that it may be due to the same mutant channel, not only being expressed in the heart but also expressed in the brain. When it's expressed in the heart it's messing up electrical function, so anywhere else where the expression has changed because of the mutation will likely result in electrical abnormalities as well.” Auerbach says this research is crucial to safely treat patients. “You have to be very careful picking drugs because people with LQTS are very prone to electrical abnormalities in the heart.” Thus, this new animal model will enable his research team to evaluate the cardiac safety of neurotherapetics.  

In the first phase of the research, the team will characterize their rabbit model by examining whether these animals exhibit the neurological and cardiac issues that model those seen in LQT2 patients with epilepsy. Next, they will investigate the effects of anti-seizure medications (ASMs), particularly those that block sodium channels like phenytoin. They will study whether these medications worsen heart rhythm problems in their novel translational rabbit model of LQT2, as has been observed in LQT2 patients on ASMs. 

You can read more about the grant here- https://reporter.nih.gov/search/Z4ehBUEbvUm0afzJBolY0A/project-details/10728653