Pharma Focus Europe

Translational Research Describes an Epigenetic Approach for Regulating Fear-Memory

Tuesday, August 23, 2022

EpiVario, Inc., an emerging biotech company dedicated to developing innovative therapeutics for memory-related psychiatric disorders, has announced significant preclinical research findings that have the potential to lead to a treatment approach for Post-Traumatic Stress Disorder (PTSD). The study, co-authored by the academic co-founders of EpiVario and published in the Proceedings of the National Academy of Sciences (PNAS), demonstrates the role of the enzyme acetyl-CoA synthetase 2 (ACSS2) in controlling fear memories. The research also confirms that inhibiting ACSS2 with a small molecule inhibitor can block the epigenetic process required for stress and fear memory consolidation.

The study, conducted at the Perelman School of Medicine at the University of Pennsylvania and led by EpiVario Co-Founder Shelley Berger, PhD, Daniel S. Och University Professor and Director of the Penn Epigenetics Institute, along with Co-Founder Philipp Mews, PhD, and postdoctoral scientist Tanya Corman, PhD, reveals the crucial role of the metabolic enzyme ACSS2 in regulating fear memory. The researchers demonstrated that the genetic deletion or pharmaceutical inhibition of ACSS2 significantly reduces the ability of mice and rats to form long-term memories of traumatic events.

The investigational small molecule compounds used in the study were provided by EpiVario, which is actively developing ACSS2 inhibitors as therapeutics for memory-related neuropsychiatric disorders. The study was made possible through collaboration with Dr. Marcelo Wood at UC Irvine and Dr. Hagit Cohen at Ben-Gurion University of the Negev, Israel.

Dr. Philipp Mews expressed excitement about the findings, stating that they validate earlier discoveries that highlighted the critical role of ACSS2 in activating genes during the formation of fear memories. The process of reconsolidation, which occurs when traumatic events are recalled, involves the activation of these genes. By temporarily blocking ACSS2 and reducing reconsolidation, it is expected that trauma memories underlying PTSD can be weakened.

Previous research conducted by Dr. Mews and his team at Berger's lab revealed that ACSS2 is a metabolic enzyme that operates within the nucleus of neurons, turning genes on during the establishment of new memories and the recollection of older memories. ACSS2 facilitates the production of acetyl-coenzyme A (acetyl-CoA), a small molecule that carries a chemical tag called acetyl group. Acetyl-CoA plays a critical role in histone acetylation, a process that controls gene activity, including the activation of genes necessary for converting short-term memories into long-term memories.

In the present study, the researchers investigated ACSS2's involvement in the formation of long-term fear memories in adult mice. They developed a line of mice in which the ACSS2 gene was disabled and observed that the absence of the gene did not impair normal short-term working memory or other mouse activities. However, it significantly reduced the strength of long-term memories, including fear memories. The researchers also confirmed that histone acetylation and gene activity changes associated with long-term memory consolidation were reduced.

In further experiments, normal mice and rats were injected with an ACSS2 inhibitor immediately before and after fear conditioning. These animals exhibited significantly less freezing behavior when exposed to reminders of the shock, indicating a reduced fear response. Importantly, the effect of the inhibitor was specific to gene activity during the treatment period, as administering the drug outside the consolidation window had no impact on memory strength.

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