EpiVario is a spin-off from the University of Pennsylvania in Philadelphia.
Severe physical or psychological trauma can leave lasting marks on the memory, long after the event occurred. Post-traumatic stress disorder (PTSD) can profoundly affect a person’s ability to sleep, work or maintain healthy relationships. Routine occurrences can reawaken the distress, years after the trauma.
Most treatments manage a person’s mental and emotional response to the trauma. But a programme from EpiVario in Philadelphia, Pennsylvania, takes a different approach — one that combines drugs and psychiatric therapy to biochemically weaken the grip of traumatic memories. “The problem is the cycle of retrieving the memory,” explains co-founder Philipp Mews. “We see amazing clinical value in the development of small-molecule agents that interfere with this cycle.”
The roots of EpiVario’s PTSD programme lie in research that Mews conducted as a graduate student in the laboratory of co-founder Shelley Berger at the University of Pennsylvania in Philadelphia. The Berger group focuses on epigenetics — chemical modifications to chromosomal DNA and the histone proteins that provide an organizing scaffold for that genetic material. These modifications, which include the addition and removal of acetyl and methyl chemical groups, can dramatically alter chromosomal structure, thereby modulating the level of gene expression.
Mews determined that an enzyme called acetyl-coenzyme A synthetase 2 (ACSS2) helps to produce the raw material required to add an acetyl group to histones. ACSS2 does not modify the histones directly, but rather generates acetyl groups that are then coupled to histones by a separate class of enzymes known as acetyltransferases. “These acetyl groups help to open up these very tight histone complexes, and make genes accessible for the gene-expression machinery,” says Mews. However, he and his colleagues showed that ACSS2 also attaches itself to specific chromosomal regions slated for the addition of an acetyl group, thereby helping to regulate which genes are turned on or off1.
Such epigenetic regulation occurs in every cell in the body, but when Mews investigated further, he revealed that ACSS2 is especially active in the mammalian hippocampus. This structure is a crucial centre for memory management in the brain, and in 2017, Mews, Berger and their colleagues demonstrated a direct link between ACSS2 and memory encoding1. “The initial finding was simply that it was required for normal learning and memory,” says Berger. “But that led to the idea that it could also be involved in unwanted memory.” Indeed, Mews and his colleagues showed that disabling the gene producing ACSS2 affected the ability of mice to encode fear memories. Compared with mice that had functioning ACSS2-producing genes, the mice with the disabled gene displayed reduced aversion to an environment in which they had previously experienced an electric shock.
A specific target
Berger and Mews launched EpiVario with the goal of targeting ACSS2 and other epigenetic modulators in people with neuropsychiatric disorders, to weaken the hold of traumatic memories. PTSD is notoriously difficult to treat, says Elisabeth Binder, a clinical researcher specializing in mood and anxiety disorders at the Max Planck Institute of Psychiatry in Munich, Germany. “It affects about 5–10% of the population, so it is common,” she says. “And it is also often treatment resistant — quite a number of patients are difficult to treat or don’t respond at all.”
Histone acetylation is a well-known lever for genes controlling memory formation and consolidation. But targeting histone acetyltransferases directly is a tricky business, given their broad activity throughout the body. By contrast, ACSS2’s largely hippocampus-specific expression could offer a more specific target. Mice without ACSS2 seem to have no ill effects beyond their impaired ability to form memories, indicating that targeted inhibition of this enzyme should generally be safe in people — if treatment can be tightly controlled. “You wouldn’t want a total knockout, because you’d impair memory continuously,” says Berger. “You want to do that on a short-term basis.” EpiVario’s current lead ACSS2 inhibitor compound achieves this goal, rapidly crossing the blood–brain barrier and entering the hippocampus. “When we inject it into the peritoneal cavity of a mouse, it appears in the brain within 30 minutes,” says Berger. Once there, it lingers for no more than an hour.
The company’s goal is to exploit this fast action and short half-life in the context of psychotherapy, by administering the drug while a clinician works with the patient to elicit the stress-inducing memories associated with PTSD. According to Mews, recalling a memory opens a window in which the recollection can be either cemented or erased (see ‘Blocking memory consolidation’). “These memories become labile for a short time, and then they actually have to be reconsolidated and laid down again,” he says. “So there’s an opportunity to transiently block this ACSS2 pathway, and prevent the laying down of the stress-memory response in PTSD-affected individuals.”
“I think this pairing of a drug with a certain sort of stimulus in a therapeutic setting could be promising,” says Binder, although she adds that it would be important to ensure that the therapeutic approach is focused on exclusively eliciting the unwanted, stress-inducing memory. “In humans, it’s not very clear how specifically you could target that in the session,” she cautions.
EpiVario is now focused on developing more-sophisticated animal models of PTSD to test its approach, and it has assembled a network of collaborators and advisers to assist this process. Hagit Cohen at Ben-Gurion University of the Negev in Beersheba, Israel, has devised a promising stress model in rats based on the fear and anxiety elicited by a predator scent — in this case, urine from cats. The company is also laying the groundwork for moving to human trials in the next few years, with guidance from clinical advisers, including Rachel Yehuda, director of the traumatic-stress-studies division at the Icahn School of Medicine at Mount Sinai in New York City. And under the leadership of chief executive Thomas Kim, former general counsel at US vaccine developer Inovio Pharmaceuticals, EpiVario is pursuing its first round of venture-capital funding to support the toxicology testing needed to file an investigational new drug application with the US Food and Drug Administration.
The company’s founders are sanguine about the challenges of drug development in the neuropsychiatric space, in which many big pharma players have opted to scale back their investment in recent years. “There is some fear and trepidation amongst investors in the whole brain area,” acknowledges Berger.
But the company is also taking care not to tie its fortunes to just one drug candidate. Mews notes that EpiVario’s researchers are developing various derivatives of the company’s PTSD agent that might be superior — such as one that can be swallowed, rather than injected into the abdomen. And over the longer term, the goal is to produce a broader drug-development platform for discovering epigenetic modulators that might be suitable for breaking neurological associations in a host of anxiety- and addiction-related disorders. Success could bring peace of mind to the many people plagued by lingering trauma. “We think this is a really nice place for discovery,” says Berger.
Mews, P. et al. Nature 546, 381–386 (2017).