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 http://www.epivario.com.
SOURCE EpiVario, Inc.