NRI D​r. Reddy Invents Epigenetic Therapy for Preventing Epilepsy
APEDB
Ramakrishna

NRI D​r. Reddy Invents Epigenetic Therapy for Preventing Epilepsy

08-02-2018

NRI D​r. Reddy Invents Epigenetic Therapy for Preventing Epilepsy

Epilepsy affects the lives of millions of people worldwide, and although breakthroughs in epilepsy research have provided individual pieces of the puzzle, researchers have yet to discover the magic bullet to permanently end the condition. However, Dr. Samba Reddy, Professor of Neuroscience and Experimental Therapeutics at Texas A&M University College of Medicine, recently published a paper suggesting that the next major puzzle piece might come from a different field altogether: cancer.

The paper, published as a cover story in the January 2018 issue of the Journal of Pharmacology and Experimental Therapeutics, is the first to apply a concept called epigenetic histone modification, a common cancer treatment, to the prevention of epileptogenesis, which is the formation of epilepsy by a precipitating event.

Epilepsy is a common brain disease, characterized by repeated unprovoked seizures, due to abnormal electrical activity in the brain. This condition affects about three million American adults and 65 million people worldwide. Approximately 150,000 new cases of epilepsy are diagnosed in the United States annually.

“When the brain suffers an injury, a person will not necessarily become epileptic immediately; that can take months to years,” Dr. Reddy said. “So, after the injury, the patient has a window of time that we call a ‘therapeutic window’ or ‘latent period’ before he or she begins experiencing chronic epilepsy. The latent period provides us an opportunity to intervene and prevent the development of chronic epilepsy. Our goal is to find and inhibit critical epileptogenic signaling pathways during this period.”

That’s where epigenetic histone modification shows promise. Epigenetic changes are alterations not in the DNA itself, but in how the genes are expressed. This process is mediated by how tightly genetic information is packaged in cells: In order to fit meters of DNA into each microscopic cell, the genetic material must be condensed in a certain way. DNA strands, which are negatively charged, are tightly wrapped around positively-charged proteins called histones, forming a coil called a nucleosome. The nucleosome further condenses to eventually form chromatin, which makes up chromosomes.

Because epigenetic changes are mediated by how tightly this chromatin is coiled, there are certain enzymes in the body that can loosen or tighten the attachment between the DNA and the histone proteins that make up the chromatin. Histone acetyltransferase (HAT) enzymes loosen the attachment between DNA and histone proteins, which makes the DNA more physically accessible to be transcribed into RNA and translated into a protein. Conversely, histone deacetylase (HDAC) enzymes tighten the attachment between DNA and histone proteins, which hinders transcription and translation.

“In cancer, HDAC activity in cells is markedly increased,” Dr. Reddy said. “So, many cancer treatments are based on HDAC blockers, because they stop the growth of cancer in part by increasing the acetylation and expression of genes which were suppressed by the cancer. Epileptogenesis has some mechanisms similar to cancer, including the proliferation of abnormal cells, inflammation and sprouting of the neurons. Our thought was that if HDAC inhibitors could prevent cell-altering mechanisms of cancer, then they could prevent similar mechanisms involved in injury-induced epilepsy.”

In the paper, Dr. Reddy and his team, which included young researchers Sandesh Reddy and Bryan Clossen, proposed that the activation of HDAC could be one common mechanism of epilepsy formation after an injury to the brain. This precipitating injury could cause increased HDAC activity, altering the transcription of some genes and thereby contributing to an electrical rewiring of the brain.

In the study, Dr. Reddy’s team used an experimental temporal lobe epilepsy model that is widely utilized by the U.S. Food and Drug Administration (FDA) for approving antiepileptic medications. The results showed that daily administration of an experimental HDAC inhibitor during the latent period significantly hindered epileptogenesis, even for weeks after discontinuing the treatment.

“These results were totally surprising,” Dr. Reddy said. “The long-lasting effects of HDAC inhibition in the brain could be the key for a new treatment to prevent epileptogenesis.”

Even more surprising to the researchers, however, was the finding that HDAC-inhibiting drug therapy also partially broke seizure-prone networks and diminished seizures in subjects with preexisting chronic epilepsy. This discovery has promising clinical significance because there is currently no medication that can reverse the epileptic state, and drugs that reduce seizure activity must be taken indefinitely to continue providing benefit.

“These results suggest that it may be feasible to erase or soften existing epilepsy by shrinking the epileptic state, such that additional treatments are not needed,” Dr. Reddy said.

Next, Dr. Reddy plans to extend this research to epilepsy resulting from traumatic brain injury, which affects many soldiers who have been in combat. He plans to use existing clinically available HDAC inhibitors, such as vorinostat, to treat post-traumatic epilepsy.

“These findings offer the possibility of rapid translation of our research from bench to bedside because FDA-approved HDAC inhibitors already exist and are commonly used to treat patients with cancer,” Dr. Reddy said.

This research has been partly supported by a grant from the U.S. Department of Defense.

Dr. Samba Reddy hails from Warangal in Telangana state, India.