A New Class of Drugs for Epilepsy —Spark Fund awardees Andrew Zorn & Diomedes Logothetis

May 8, 2023 | Available Tech, Recognition, Spark Fund

Logothetis Lab

Dravet Syndrome (DS) is a rare and debilitating genetic disorder that affects approximately one in every 15,000-20,000 individuals worldwide. It is a pediatric condition that can start as early as six months of age. This disorder is characterized by frequent and prolonged seizures that are often difficult to control with medication. It is also characterized by cognitive and developmental delays and other neurological and physical impairments, and carries a considerable risk of sudden, unexplained death from epilepsy (SUDEP). Unfortunately, there are currently no known cures for DS and current FDA-approved treatments are ineffective and poorly tolerated by the patients. This leaves many individuals and their families struggling to manage the symptoms and maintain a good quality of life.

That’s why Northeastern Professor Diomedes Logothetis, Ph.D. and his team, including Andrew Zorn, M.S. are developing small molecule drug candidates to help balance neuronal activity, reduce epileptic seizures, and mitigate the risk of off-target effects and toxicities from treatment. This work has secured their spot as one of the Fall 2022 Spark Fund awardees.

Balancing Neurons by Targeting Ion Channels with Small Molecule Drugs

The research began in the lab of Dr. Diomedes Logothetis over 30 years ago, as Dr. Logothetis has been elucidating the mechanism of ion channel gating throughout his career. Today, the Logothetis lab aims to reduce seizures in pediatric epilepsy patients by restoring balance within hyperexcited neurons. They target proteins on the cell surface that move ions across the cell membrane with novel small molecules by using mechanistic insights from both computational and experimental approaches.

In a properly functioning brain, the firing of inhibitory and excitatory neurons maintains a balance in electrical activity. However, in DS, there are silencing mutations in sodium channels that can turn off the inhibitory interneurons and therefore cause an imbalance and hyperexcitability that causes seizures. The team’s drug candidates can reduce hyperexcitability and restore balance by selectively acting on the ion channels found in the regions of the brain associated with seizure generation. Specifically, the team is focused on the molecular details of how the signaling membrane phospholipid, PIP2, controls the gating of ion channels, such as the G-protein gated inwardly rectifying K+ channels (GIRKs).

GIRK activation inhibits excitability and is involved in conditions, such as epilepsy, pain/opioid addiction, and cardiac arrhythmias, like atrial fibrillation. Small molecule drugs can activate GIRKs allosterically. Computer simulations of GIRKs with PIP2 and small molecule activators have captured the details of channel gating, offering a platform for dynamic structure-based drug design. By understanding how these ion channels work at the atomic level, the team aims to develop novel small molecules that specifically and selectively target specific ion channels and further develop them into drugs.

“Once we realized the potential in drugging ion channels using our approach, we decided to focus on diseases that had unmet needs,” says Zorn. “Many of those diseases are rare diseases and even more necessary are rare diseases that affect young patients. Because we can look at many diseases and use the same approach, we felt it important to our mission to first focus on rare diseases in pediatrics to see if we can’t change the lives of these young patients and their caregivers.”

Commercialization with the Spark Fund

The team is working to lead the development of an entirely new class of anti-epileptic drugs that are more efficacious and tolerable to patients. Their drug candidates have the potential to be scaled to almost any type of epilepsy — not just the rare pediatric epilepsies that are their initial indications. Furthermore, by using the novel approach of allosteric modulation of ion channels, the team can target many other disease indications in the future.

Through commercialization and the help of the Spark Fund, the team is working to get the first drug to the market in the next 5-10 years while also be developing additional drugs for new indications. “Establishing an organization that can support the development of a drug sounds relatively straightforward on paper, but success requires learning a lot about disciplines outside of science,” says Zorn. “Understanding everything well enough to build a strong organization takes an immense amount of time and commitment. Furthermore, selling your story to outsiders differs greatly from telling your story to insiders. Therefore, CRI has been extremely helpful to our commercialization efforts. We have been able to tap into additional resources and groups on the Northeastern campus through the CRI that we would not have known existed otherwise.”

The Spark Funds and support from CRI will help fund further scientific studies, strengthen the team’s data package, and ultimately help the team pitch investors and secure future funding, such as a significant Series A round, to get their drug candidate to the clinic. “With the CRI, we feel like we have a whole team in our corner supporting us and rooting for our success,” says Zorn.

Learn more about the Logothetis lab’s research and the other Spark Fund Award grantees here.