PHILADELPHIA, Oct. 23, 2019 /PRNewswire-PRWeb/ -- EpiVario, Inc., an early-stage drug discovery and development company, today announced results published in Nature, co-authored by the co-founders of EpiVario, which showed that alcohol consumption directly influences epigenetic regulation essential to memory formation. Through this metabolic route to epigenetic regulation, the studied animals showed preference for alcohol when exposed to environmental cues to consume alcohol; and when this metabolic route was blocked, this preference was eliminated.

The underlying study was conducted at the Perelman School of Medicine at the University of Pennsylvania and was led by Co-Founder Shelley Berger, PhD, Daniel S. Och University Professor and Director of the Penn Epigenetics Program, and Co-Founder Philipp Mews, PhD, who is now a postdoctoral fellow at The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York.

The research used isotopically-labeled alcohol and advanced mass spectrometry to track where the alcohol, and its breakdown products, go in the body and the brain. By doing so, metabolized alcohol was discovered to rapidly impact histone acetylation in the hippocampus – the learning and memory center of the brain – by directly depositing alcohol-derived acetyl groups onto histones via an enzyme called acetyl-CoA synthetase 2 (ACSS2).

Previous research conducted in the Berger lab, and led by Dr. Mews, found that ACSS2 is a key metabolic enzyme that works directly within the nucleus of neurons to turn genes on when new memories are being established.

"Our team in the Berger lab had previously discovered that ACSS2 'fuels' a whole new machinery of gene expression 'on-site' in the nucleus of brain cells to turn on key memory genes after learning," said Dr. Mews of the work that was published in a 2017 Nature paper. "We learned then that the metabolic factor ACSS2 is needed to lay down new memories."

Combined with the results of the current study, this suggests an entirely new route by which alcohol directly affects the brain via the ACSS2 enzyme and causes alcohol-related learning. Targeting this route could eventually aid in treating alcohol use disorder (AUD) and fetal alcohol syndrome (FAS).

Memories associated with alcohol consumption are a primary driver of alcohol use disorder. According to the National Institute on Alcohol Abuse and Alcoholism, the disorder affects 15.1 million people in the United States alone, with the cost of alcohol misuse hovering at $250 billion.

"To our knowledge, this data provides the first empirical evidence indicating that a portion of the chemicals called acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain," said Dr. Berger. "The team was surprised to find that metabolized alcohol is directly used by the body to add acetyl groups to the proteins that package DNA, called histones, which is a key component in the memory formation process."

In the current study, mice were exposed to neutral and alcohol reward spaces in designated compartments of their living environment to better understand how memories of alcohol-associated cues can affect behavior. The mice were allowed to roam free and researchers recorded the amount of time spent in either compartment. Mice with normal ACSS2 activity in their brains spent more time in the alcohol compartment. However, when ACSS2 in the brain was reduced, their preference for the alcohol compartment was not favored over the neutral compartment.

"This is significant because in alcohol use disorders, memory of alcohol-associated cues is a primary driver of craving and relapse, even after prolonged periods of abstinence," said Dr. Mews. "Our latest findings establish a direct link between alcohol metabolism and histone acetylation in the hippocampus, indicating that translational treatment strategies that target this metabolic-epigenetic nexus may pave the way for novel therapeutic interventions for alcohol use and other neuropsychiatric disorders."

The study also looked at the effects of alcohol consumption on developing mice by examining pregnant mice. After exposing the pregnant mice to 'binge-drinking' levels of alcohol, researchers identified deposits of alcohol-derived acetyl-groups onto histones in the fetal brains. These findings could eventually support the treatment and prevention of fetal alcohol syndrome, a cause of postnatal developmental disorders.

Thomas Kim, President and CEO of EpiVario, expressed the excitement over this data, saying, "The results further show the importance of ACSS2 as a target for preventing the storage of unwanted memories, in this case the cravings for alcohol triggered by environmental cues."

EpiVario exclusively licensed the intellectual property related to this work from the University of Pennsylvania. In addition to their current work on the development of a treatment for AUD, EpiVario is also developing a small molecule therapeutic for PTSD.

About EpiVario, Inc.
EpiVario is an early-stage drug discovery and development company that targets a wide range of memory-related psychiatric disorders, including PTSD, Alzheimer's, and alcohol and drug addiction. The Company's novel approach targets memory formation at the source of the disease, preventing the creation and reconsolidation of traumatic memories. Core to EpiVario is administering its drug in conjunction with psychotherapy, where a negative or traumatic memory is intentionally re-lived, with the goal of disassociating the stress linked to the original traumatic event. EpiVario is a startup company originally founded at the Penn Center for Innovation. For more information visit


SOURCE EpiVario, Inc.

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