Emerging U.S. biotech company EpiVario, Inc. has highlighted preclinical research findings that could lead to a treatment approach for post-traumatic stress disorder (PTSD).
Published in Proceedings of the National Academy of Sciences (PNAS), and co-authored by the academic co-founders of EpiVario, the study demonstrates that fear memories can be controlled through the enzyme acetyl-CoA synthetase 2 (ACSS2). The team also confirmed that a small molecule inhibitor against ACSS2 can block the epigenetic process required for the consolidation of stress and fear memories.
In the study, the researchers identified the metabolic enzyme ACSS2 as a key regulator of fear memory, and showed that genetic deletion or pharmaceutical inhibition of ACSS2 greatly reduces the ability of mice and rats to form long-term memories of trauma events.
The study was conducted at the Perelman School of Medicine at the University of Pennsylvania and was led by EpiVario co-founder Shelley Berger, Daniel S. Och university professor and director of the Penn Epigenetics Institute, and co-founder Philipp Mews, currently an instructor at The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York, along with Tanya Corman, a postdoctoral scientist at the University of Pennsylvania.
Developing ACSS2 inhibitors
Investigational small molecule compounds were provided by EpiVario, which is developing ACSS2 inhibitors as a therapeutic for memory related neuropsychiatric disorders. The work was further enabled through EpiVario collaborators Marcelo Wood at UC Irvine, and Hagit Cohen at Ben-Gurion University of the Negev, Israel.
“These new results are exciting, as they validate our earlier discovery that ACSS2 is critical for activating genes during the creation of fear memories. Similarly, whenever we recall a traumatic event, these genes are activated in the same way, a process called reconsolidation, which is important in PTSD. In principle, reducing that reconsolidation by briefly blocking ACSS2, we expect to weaken trauma memories that underlie PTSD,” Mews said.
Previous research conducted in Berger’s lab, and led by Mews, found that ACSS2 is a key metabolic enzyme that works within the nucleus of neurons to turn genes on when new memories are being established, and also after older memories are recalled.
ACSS2 catalyzes the production of acetyl-coenzyme A (acetyl-CoA), a small molecule that serves as a cellular carrier of a chemical tag called acetyl group. Among its many actions, acetyl-CoA uses its acetyl payload to carry out a process called histone acetylation, which controls gene activity—including the gene activity needed to turn short-term memories into long-term memories.
In the present study, the researchers investigated ACSS2’s role in forming long-term fear memories in adult mice. The team first developed a line of mice in which the ACSS2 gene was disabled. They found that the absence of the gene did not impair ordinary, short-term working memory or other mouse activities, but did significantly reduce the strength of long-term memories, including fear memories.
The researchers also confirmed a reduction of histone acetylation and gene activity changes normally associated with long-term memory consolidation.
Potential stress reduction
“These new findings support our approach of inhibiting ACSS2 as a therapeutic target to potentially reduce stress associated with traumatic memory,” said Berger, senior author of the study.
Next, the team injected normal mice and rats, immediately before and after fear-conditioning, with a compound that blocks ACSS2 activity for a brief period of time. Compared to untreated rodents, the treated animals showed significantly less freezing behavior when presented with shock-reminder cues. Importantly, the effect of the inhibitor was specific to gene activity during the treatment period—drug administered outside the consolidation window had no impact on the strength of memories formed.
Lastly, the scientists used a rat model of PTSD, in which rats are exposed to a predator scent (cat urine) and tested a week later for heightened signs of anxiety when exposed to the scent. Here again, the presence of the ACSS2 inhibitor during the memory-consolidation window reduced subsequent anxiety signs in the treated rats, compared to control rats.
“These research findings continue to encourage the team at EpiVario, since they provide significant additional in vivo validation of EpiVario’s therapeutic approach, and further underscore the importance of ACSS2 as a target for attenuating fear memories, which we believe could be a transformative approach for the treatment of PTSD,” said Thomas Kim, president and CEO of EpiVario.
“It is exciting to see EpiVario’s work progress through targeting fear-related neuroplasticity and the formation of fear memories,” said John Krystal, EpiVario SAB member, and chair of Psychiatry at Yale University.
“We urgently need new treatments for PTSD, and need to explore innovative new therapeutic strategies, with ACSS2 inhibition representing a novel strategy that holds significant promise.”