SCIENCE science.orgnections, sculpting new brain circuits that
encode the memory. This finding led to the
idea that ACSS2 could be involved in un-
wanted memory formation. We confirmed
this idea by showing that blocking ACSS2
affected the ability of mice to encode fear
memories. Animals without the active en-
zyme displayed reduced aversion to an envi-
ronment in which they had previously expe-
rienced an electric shock. The mice lacking
ACSS2 are also completely healthy beyond
their impaired memory. Because this work
had great clinical promise, we formed our
company to bring new treatments to people
with disorders associated with traumatic or
burdensome memories.
We launched EpiVario to target ACSS2 in
people with posttraumatic stress disorder
(PTSD) to diminish their traumatic memo-
ries. PTSD can develop after events such as
interpersonal violence, combat, or even the
physical and emotional stress linked to se-
vere cases of COVID-19. Symptoms include
intrusive retrieval of traumatic memories,
insomnia, and irritability. Unfortunately,
current treatments are desperately insuffi-
cient. EpiVario aims to treat patients dur-
ing psychotherapy sessions, by administer-
ing the drug as a clinician works with the
patient to elicit the stress-inducing memo-
ries. Recall of the traumatic event opens
a window during which recollection can
either reinforce or weaken the memory.
Our product is a short-lived drug that read-
ily crosses the blood-brain barrier to tran-
siently block the ACSS2 pathway. EpiVario’s
goal is to reduce the stress associated with
the unwanted trauma memory through
treatment that provides a lasting effect.
The company’s intellectual property is well
protected. The pathway and mode of ac-
tion were previously unknown, and patents
were exclusively licensed worldwide from
the University of Pennsylvania, where our
spin-off was incubated.
Our recognition that acetate metabolism
is closely linked to learning and memory in-
spired us to explore a nutrient well known
for altering memory: alcohol. When con-
sumed, alcohol is metabolized in the liver
and causes a surge in circulating acetate
( 5 ). We hypothesized that this acetate spike
might fuel ACSS2-driven acetylation of neu-
ronal genes. In mice injected with isotopi-
cally labeled alcohol, we used mass spec-
trometry to track alcohol molecules as they
traveled throughout the body. Minutes after
alcohol consumption, we detected labeled
acetate on histones within neurons, indicat-
ing a link between liver alcohol metabolism
and gene regulation in the brain ( 5 ).Bringing the two research areas together
synergistically, we hope to target memo-
ries linked to substance use disorders ( 5 ,
6 ). When ACSS2 is blocked in the mouse
brain, alcohol was prevented from contrib-
uting to gene activation, confirming that
its metabolites play an important role in
controlling how alcohol affects our mem-
ory (see the figure). Mice with lowered
ACSS2 do not form a preference for envi-
ronments where they have been given al-
cohol. These findings are notable because
the memory of alcohol-associated cues is
a primary driver of craving and relapse in
people with alcohol use disorder ( 7 ).
Memory-related diseases are insidious
and often share a common ability to silently
erode joy from our lives. In the past, PTSD
and substance use disorders were frequently
written off as moral failures of character,
but today they are recognized as complex
disorders with biological underpinnings.
Our research shows that trauma and
stress memory are influenced by a link
between nutrient metabolism and histone
acetylation in the brain. EpiVario is devel-
oping future therapeutics that target this
link to treat memory-related disorders, in-
cluding PTSD; alcohol addiction; and, most
recently, smoking cessation. In the future,
our company aims to build a broader drug-
development platform for screening epi-
genetic enzymes that could be suitable for
modulating neuronal processes in a host of
anxiety and addiction disorders.
Our research further suggests that other
external sources of acetate (e.g., sour foods
and various gut microbiota) may similarly
affect histone acetylation to modulate mem-
ory. Exploring the ways that our metabo-
lism can shape genes and neural circuits
promises to improve our understanding of
mental health and disease. As we continue
to raise money to fund our forthcoming
clinical trials, we are driven by our passion
for having a positive impact on the many
individuals affected by traumatic memories
and addiction. jREFERENCES AND NOTES- P. Mews et al., Nature 546 , 381 (2017).
- P. Mews et al., J. Neurosci. 41 , 873 (2021).
- E. J. Nestler, C. Lüscher, Neuron 102 , 48 (2019).
- J. Gräff, L.-H. Tsai, Nat. Rev. Neurosci. 14 , 97 (2013).
- P. Mews et al., Nature 574 , 717 (2019).
- S. C. Pandey, E. J. Kyzar, H. Zhang, Neuropharmacology
122 , 74 (2017). - G. F. Koob, N. D. Volkow, Lancet Psychiatry 3 , 760 (2016).
10.1126/science.abo4234
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Email: [email protected]8 APRIL 2022 • VOL 376 ISSUE 6589 147-A0408PrizeEssay_15347997.indd 149 4/1/22 4:36 PM